Modulators of pharmacokinetic properties of therapeutics

ABSTRACT

The present application provides for a compound of Formula I, 
                         
or a pharmaceutically acceptable salt, solvate, and/or ester thereof, compositions containing such compounds, therapeutic methods that include the administration of such compounds, and therapeutic methods and include the administration of such compounds with at least one additional therapeutic agent.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application Ser.No. 60/832,371, entitled “Modulators of Pharmacokinetic Properties ofTherapeutics”, filed Jul. 21, 2006, U.S. Provisional Application Ser.No. 60/819,315, entitled “Modulators of Pharmacokinetic Properties ofTherapeutics”, filed Jul. 7, 2006, and U.S. Provisional Application Ser.No. 60/903,228, entitled “Modulators of Pharmacokinetic Properties ofTherapeutics”, filed Feb. 23, 2007. The contents of these provisionalapplications are herein incorporated by reference in their entirety forall purposes.

FIELD OF THE INVENTION

This application relates generally to compounds and pharmaceuticalcompositions which modify, e.g., improve, the pharmacokinetics of aco-administered drug, and methods of modifying, e.g., improving, thepharmacokinetics of a drug by co-administration of the compounds withthe drug.

BACKGROUND OF THE INVENTION

Oxidative metabolism by cytochrome P450 enzymes is one of the primarymechanisms of drug metabolism. It can be difficult to maintaintherapeutically effective blood plasma levels of drugs which are rapidlymetabolized by cytochrome P450 enzymes. Accordingly, the blood plasmalevels of drugs which are susceptible to cytochrome P450 enzymedegradation can be maintained or enhanced by co-administration ofcytochrome P450 inhibitors, thereby improving the pharmacokinetics ofthe drug.

While certain drugs are known to inhibit cytochrome P450 enzymes, moreand/or improved inhibitors for cytochrome P450 monooxygenase aredesirable. Particularly, it would be desirable to have cytochrome P450monooxygenase inhibitors which do not have appreciable biologicalactivity other than cytochrome P450 inhibition. Such inhibitors can beuseful for minimizing undesirable biological activity, e.g., sideeffects. In addition, it would be desirable to have P450 monooxygenaseinhibitors that lack significant or have a reduced level of proteaseinhibitor activity. Such inhibitors could be useful for enhancing theeffectiveness of antiretroviral drugs, while minimizing the possibilityof eliciting viral resistance, especially against protease inhibitors.

SUMMARY OF THE INVENTION

One aspect of the present application is directed to compounds andpharmaceutical compositions which modify, e.g., improve, thepharmacokinetics of a co-administered drug, e.g., by inhibitingcytochrome P450 monooxygenase.

In one embodiment, the present application provides for compounds havinga structure according to Formula I:

-   or a pharmaceutically acceptable salt, solvate, and/or ester    thereof, wherein,-   L¹ is selected from the group consisting of —C(R⁶)₂—, —C(O)—,    —S(O)₂—, —N(R⁷)—C(O)—, and —O—C(O)—;-   L² is a covalent bond, —C(R⁶)₂— or —C(O)—;-   each L³ is independently a covalent bond, an alkylene, or    substituted alkylene;-   each L⁴ is independently selected from the group consisting of a    covalent bond, alkylene, substituted alkylene, —O—, —CH₂—O—, and    —NH—;-   each A is independently selected from the group consisting of H,    alkyl, substituted alkyl, aryl, substituted aryl, heterocyclyl, and    substituted heterocyclyl,    -   with the proviso that when A is H, p is 0;-   Z¹ and Z² are each independently —O— or —N(R⁷)—;-   Y and X are independently selected from the group consisting of    heterocyclyl and heterocyclylalkyl;-   each Ar is independently selected from the group consisting of aryl,    substituted aryl, heteroaryl, and substituted heteroaryl;-   R¹, R³, and R⁵ are each independently selected from the group    consisting of H, alkyl, substituted alkyl, arylalkyl, and    substituted arylalkyl;-   each R² is independently selected from the group consisting of H,    alkyl, substituted alkyl, alkoxyalkyl, hydroxyalkyl,    arylheteroalkyl, substituted arylheteroalkyl, arylalkyl, substituted    arylalkyl, heterocyclylalkyl, substituted heterocyclylalkyl,    aminoalkyl, substituted aminoalkyl, -alkylene-C(O)—OH,    -alkylene-C(O)—Oalkyl, -alkylene-C(O)amino, -alkylene-C(O)-alkyl;-   R⁴ and R⁶ are independently selected from the group consisting of H,    alkyl, substituted alkyl, and heteroalkyl;-   each R⁷ is independently selected from the group consisting of H,    alkyl, substituted alkyl, heteroalkyl, carbocyclyl, substituted    carbocyclyl, heterocyclyl, and substituted heterocyclyl;-   R⁸ and R⁹ are each one or more substituents independently selected    from the group consisting of H, alkyl, substituted alkyl, halogen,    aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, and    —CN;    -   m is 1 or 2;    -   n is 0 or 1; and    -   each p is independently 0 or 1.

In another embodiment, the present application provides for apharmaceutical composition comprising a compound of Formula I, and apharmaceutically acceptable carrier or excipient.

In another embodiment, the present application provides for apharmaceutical composition comprising a compound of Formula I, at leastone additional therapeutic agent, and a pharmaceutically acceptablecarrier or excipient.

In another embodiment, the present application provides for a method forimproving the pharmacokinetics of a drug, comprising administering to apatient treated with said drug, a therapeutically effective amount of acompound of Formula I, or a pharmaceutically acceptable salt, solvate,and/or ester thereof.

In another embodiment, the present application provides for a method forinhibiting cytochrome P450 monooxygenase in a patient comprisingadministering to a patient in need thereof an amount of a compound ofFormula I, or a pharmaceutically acceptable salt, solvate, and/or esterthereof, effective to inhibit cytochrome P450 monooxygenase.

In another embodiment, the present application provides for a method fortreating a viral infection, e.g., HIV, comprising administering to apatient in need thereof a therapeutically effective amount of a compoundof Formula I, or a pharmaceutically acceptable salt, solvate, and/orester thereof, in combination with a therapeutically effective amount ofone or more additional therapeutic agents which are metabolized bycytochrome P450 monooxygenase, and are suitable for treating a viralinfection, e.g., HIV.

In another embodiment, the present application provides for acombination pharmaceutical agent comprising:

a) a first pharmaceutical composition comprising a compound of FormulaI, or a pharmaceutically acceptable salt, solvate, and/or ester thereof;and

b) a second pharmaceutical composition comprising at least oneadditional active agent which is metabolized by cytochrome P450monooxygenase.

DETAILED DESCRIPTION

Reference will now be made in detail to certain claims of the invention,examples of which are illustrated in the accompanying structures andformulas. While the invention will be described in conjunction with theenumerated claims, it will be understood that they are not intended tolimit the invention to those claims. On the contrary, the invention isintended to cover all alternatives, modifications, and equivalents,which may be included within the scope of the present invention asdefined by the claims.

DEFINITIONS

Unless stated otherwise, the following terms and phrases as used hereinare intended to have the following meanings:

When trade names are used herein, applicants intend to independentlyinclude the tradename product and the active pharmaceuticalingredient(s) of the tradename product.

As used herein, “a compound of the invention” or “a compound of formula(I)” means a compound of formula (I) or a pharmaceutically acceptablesalt, solvate, ester or stereoisomer thereof, or a physiologicallyfunctional derivative thereof. Similarly, with respect to isolatableintermediates, the phrase “a compound of formula (number)” means acompound of that formula and pharmaceutically acceptable salts, solvatesand physiologically functional derivatives thereof.

“Alkyl” is hydrocarbon containing normal, secondary, tertiary or cycliccarbon atoms. For example, an alkyl group can have 1 to 20 carbon atoms(i.e, C₁-C₂₀ alkyl), 1 to 10 carbon atoms (i.e., C₁-C₁₀ alkyl), or 1 to6 carbon atoms (i.e., C₁-C₆ alkyl). Examples of suitable alkyl groupsinclude, but are not limited to, methyl (Me, —CH₃), ethyl (Et, —CH₂CH₃),1-propyl (n-Pr, n-propyl, —CH₂CH₂CH₃), 2-propyl (i-Pr, i-propyl,—CH(CH₃)₂), 1-butyl (n-Bu, n-butyl, —CH₂CH₂CH₂CH₃), 2-methyl-1-propyl(i-Bu, i-butyl, —CH₂CH(CH₃)₂), 2-butyl (s-Bu, s-butyl, —CH(CH₃)CH₂CH₃),2-methyl-2-propyl (t-Bu, t-butyl, —C(CH₃)₃), 1-pentyl (n-pentyl,—CH₂CH₂CH₂CH₂CH₃), 2-pentyl (—CH(CH₃)CH₂CH₂CH₃), 3-pentyl(—CH(CH₂CH₃)₂), 2-methyl-2-butyl (—C(CH₃)₂CH₂CH₃), 3-methyl-2-butyl(—CH(CH₃)CH(CH₃)₂), 3-methyl-1-butyl (—CH₂CH₂CH(CH₃)₂), 2-methyl-1-butyl(—CH₂CH(CH₃)CH₂CH₃), 1-hexyl (—CH₂CH₂CH₂CH₂CH₂CH₃), 2-hexyl(—CH(CH₃)CH₂CH₂CH₂CH₃), 3-hexyl (—CH(CH₂CH₃)(CH₂CH₂CH₃)),2-methyl-2-pentyl (—C(CH₃)₂CH₂CH₂CH₃), 3-methyl-2-pentyl(—CH(CH₃)CH(CH₃)CH₂CH₃), 4-methyl-2-pentyl (—CH(CH₃)CH₂CH(CH₃)₂),3-methyl-3-pentyl (—C(CH₃)(CH₂CH₃)₂), 2-methyl-3-pentyl(—CH(CH₂CH₃)CH(CH₃)₂), 2,3-dimethyl-2-butyl (—C(CH₃)₂CH(CH₃)₂),3,3-dimethyl-2-butyl (—CH(CH₃)C(CH₃)₃, and octyl (—(CH₂)₇CH₃).

“Alkoxy” means a group having the formula —O-alkyl, in which an alkylgroup, as defined above, is attached to the parent molecule via anoxygen atom. The alkyl portion of an alkoxy group can have 1 to 20carbon atoms (i.e., C₁-C₂₀ alkoxy), 1 to 12 carbon atoms (i.e., C₁-C₁₂alkoxy), or 1 to 6 carbon atoms (i.e., C₁-C₆ alkoxy). Examples ofsuitable alkoxy groups include, but are not limited to, methoxy (—O—CH₃or —OMe), ethoxy (—OCH₂CH₃ or —OEt), t-butoxy (—O—C(CH₃)₃ or —OtBu) andthe like.

“Haloalkyl” is an alkyl group, as defined above, in which one or morehydrogen atoms of the alkyl group is replaced with a halogen atom. Thealkyl portion of a haloalkyl group can have 1 to 20 carbon atoms (i.e.,C₁-C₂₀ haloalkyl), 1 to 12 carbon atoms (i.e., C₁-C₁₂ haloalkyl), or 1to 6 carbon atoms (i.e., C₁-C₆ alkyl). Examples of suitable haloalkylgroups include, but are not limited to, —CF₃, —CHF₂, —CFH₂, —CH₂CF₃, andthe like.

“Alkenyl” is a hydrocarbon containing normal, secondary, tertiary orcyclic carbon atoms with at least one site of unsaturation, i.e. acarbon-carbon, sp² double bond. For example, an alkenyl group can have 2to 20 carbon atoms (i.e., C₂-C₂₀ alkenyl), 2 to 12 carbon atoms (i.e.,C₂-C₁₂ alkenyl), or 2 to 6 carbon atoms (i.e., C₂-C₆ alkenyl). Examplesof suitable alkenyl groups include, but are not limited to, ethylene orvinyl (—CH═CH₂), allyl (—CH₂CH═CH₂), cyclopentenyl (—C₅H₇), and5-hexenyl (—CH₂CH₂CH₂CH₂CH═CH₂).

“Alkynyl” is a hydrocarbon containing normal, secondary, tertiary orcyclic carbon atoms with at least one site of unsaturation, i.e. acarbon-carbon, sp triple bond. For example, an alkynyl group can have 2to 20 carbon atoms (i.e., C₂-C₂₀ alkynyl), 2 to 12 carbon atoms (i.e.,C₂-C₁₂ alkyne,), or 2 to 6 carbon atoms (i.e., C₂-C₆ alkynyl). Examplesof suitable alkynyl groups include, but are not limited to, acetylenic(—C≡CH), propargyl (—CH₂C≡CH), and the like.

“Alkylene” refers to a saturated, branched or straight chain or cyclichydrocarbon radical having two monovalent radical centers derived by theremoval of two hydrogen atoms from the same or two different carbonatoms of a parent alkane. For example, an alkylene group can have 1 to20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms. Typicalalkylene radicals include, but are not limited to, methylene (—CH₂—),1,1-ethyl (—CH(CH₃)—), 1,2-ethyl (—CH₂CH₂—), 1,1-propyl (—CH(CH₂CH₃)—),1,2-propyl (—CH₂CH(CH₃)—), 1,3-propyl (—CH₂CH₂CH₂—), 1,4-butyl(—CH₂CH₂CH₂CH₂—), and the like.

“Alkenylene” refers to an unsaturated, branched or straight chain orcyclic hydrocarbon radical having two monovalent radical centers derivedby the removal of two hydrogen atoms from the same or two differentcarbon atoms of a parent alkene. For example, and alkenylene group canhave 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms.Typical alkenylene radicals include, but are not limited to,1,2-ethylene (—CH═CH—).

“Alkynylene” refers to an unsaturated, branched or straight chain orcyclic hydrocarbon radical having two monovalent radical centers derivedby the removal of two hydrogen atoms from the same or two differentcarbon atoms of a parent alkyne. For example, an alkynylene group canhave 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms.Typical alkynylene radicals include, but are not limited to, acetylene(—C≡C—), propargyl (—CH₂C≡C—), and 4-pentynyl (—CH₂CH₂CH₂C≡CH—).

“Amino” means an —NH₂ or a —NR₂ group in which the “R” groups areindependently H, alkyl, carbocyclyl (substituted or unsubstituted,including saturated or partially unsaturated cycloalkyl and arylgroups), heterocyclyl (substituted or unsubstituted, including saturatedor unsaturated heterocycloalkyl and heteroaryl groups), arylalkyl(substituted or unsubstituted) or arylalkyl (substituted orunsubstituted) groups. Non-limiting examples of amino groups include—NH₂, —NH(alkyl), —NH(carbocyclyl), —NH(heterocyclyl), —N(alkyl)₂,—N(carbocyclyl)₂, —N(heterocyclyl)₂, —N(alkyl)(carbocyclyl),—N(alkyl)(heterocyclyl), —N(carbocyclyl)(heterocyclyl), etc., whereinalkyl, carbocyclyl, and heterocyclyl can be substituted or unsubstitutedand as defined and described herein. “Substituted” or “protected” aminomeans an aminoalkyl as described and defined herein in which a H of theamino group is replaced with e.g., acyl groups, for example conventionalamine protecting groups such as 9-Fluorenylmethyl carbamate (“Fmoc”),t-Butyl carbamate (“Boc”), Benzyl carbamate (“Cbz”), acetyl,trifluoracetyl, phthalimidyl, triphenylmethyl, p-Toluenesulfonyl(“Tosyl”), methylsulfonyl (“mesyl”), etc.

“Aminoalkyl” means an acyclic alkyl radical in which one of the hydrogenatoms bonded to a carbon atom, typically a terminal or sp³ carbon atom,is replaced with an amino radical as defined and described herein.Non-limiting examples of aminoalkyl include —CH₂—NH₂, —CH₂CH₂—NH₂,—CH₂CH₂CH₂—NH₂, —CH₂CH₂CH₂CH₂—NH₂, —CH₂CH(CH₃)—NH₂, —CH₂CH₂CH(CH₃)—NH₂,—CH₂—NH(CH₃), —CH₂CH₂—NH(CH₃), —CH₂CH₂CH₂—NH(CH₃),—CH₂CH₂CH₂CH₂—NH(CH₃), —CH₂CH(CH₃)—NH(CH₃), —CH₂CH₂CH(CH₃)—NH(CH₃),—CH₂—N(CH₃)₂, —CH₂CH₂—N(CH₃)₂, —CH₂CH₂CH₂—N(CH₃)₂,—CH₂CH₂CH₂CH₂—N(CH₃)₂, —CH₂CH(CH₃)—N(CH₃)₂, —CH₂CH₂CH(CH₃)—N(CH₃)₂,—CH₂—NH(CH₂CH₃), —CH₂CH₂—NH(CH₂CH₃), —CH₂CH₂CH₂—NH(CH₂CH₃),—CH₂CH₂CH₂CH₂—NH(CH₂CH₃), —CH₂CH(CH₃)—NH(CH₂CH₃),—CH₂CH₂CH(CH₃)—NH(CH₂CH₃), —CH₂—N(CH₂CH₃)₂, —CH₂CH₂—N(CH₂CH₃)₂,—CH₂CH₂CH₂—N(CH₂CH₃)₂, —CH₂CH₂CH₂CH₂—N(CH₂CH₃)₂, —CH₂CH(CH₃)—N(CH₂CH₃)₂,—CH₂CH₂CH(CH₃)—N(CH₂CH₃)₂, etc. “Substituted” or “protected” aminoalkylmeans an aminoalkyl as described and defined herein in which the H ofthe amino group is replaced with e.g., acyl groups, for exampleconventional amine protecting groups such as 9-Fluorenylmethyl carbamate(“Fmoc”), t-Butyl carbamate (“Boc”), Benzyl carbamate (“Cbz”), acetyl,trifluoracetyl, phthalimidyl, triphenylmethyl, p-Toluenesulfonyl(“Tosyl”), methylsulfonyl (“mesyl”), etc.

“Aryl” means an aromatic hydrocarbon radical derived by the removal ofone hydrogen atom from a single carbon atom of a parent aromatic ringsystem. For example, an aryl group can have 6 to 20 carbon atoms, 6 to14 carbon atoms, or 6 to 12 carbon atoms. Typical aryl groups include,but are not limited to, radicals derived from benzene (e.g., phenyl),substituted benzene, naphthalene, anthracene, biphenyl, and the like.

“Arylalkyl” refers to an acyclic alkyl radical in which one of thehydrogen atoms bonded to a carbon atom, typically a terminal or sp³carbon atom, is replaced with an aryl radical. Typical arylalkyl groupsinclude, but are not limited to, benzyl, 2-phenylethan-1-yl,naphthylmethyl, 2-naphthylethan-1-yl, naphthobenzyl,2-naphthophenylethan-1-yl and the like. The arylalkyl group can comprise6 to 20 carbon atoms, e.g., the alkyl moiety is 1 to 6 carbon atoms andthe aryl moiety is 6 to 14 carbon atoms.

“Arylalkenyl” refers to an acyclic alkenyl radical in which one of thehydrogen atoms bonded to a carbon atom, typically a terminal or sp³carbon atom, but also an sp² carbon atom, is replaced with an arylradical. The aryl portion of the arylalkenyl can include, for example,any of the aryl groups disclosed herein, and the alkenyl portion of thearylalkenyl can include, for example, any of the alkenyl groupsdisclosed herein. The arylalkenyl group can comprise 6 to 20 carbonatoms, e.g., the alkenyl moiety is 1 to 6 carbon atoms and the arylmoiety is 6 to 14 carbon atoms.

“Arylalkynyl” refers to an acyclic alkynyl radical in which one of thehydrogen atoms bonded to a carbon atom, typically a terminal or sp³carbon atom, but also an sp carbon atom, is replaced with an arylradical. The aryl portion of the arylalkynyl can include, for example,any of the aryl groups disclosed herein, and the alkynyl portion of thearylalkynyl can include, for example, any of the alkynyl groupsdisclosed herein. The arylalkynyl group can comprise 6 to 20 carbonatoms, e.g., the alkynyl moiety is 1 to 6 carbon atoms and the arylmoiety is 6 to 14 carbon atoms.

The term “substituted” in reference to alkyl, alkylene, aryl, arylalkyl,heterocyclyl, heteroaryl, carbocyclyl, etc., for example, “substitutedalkyl”, “substituted alkylene”, “substituted aryl”, “substitutedarylalkyl”, “substituted heterocyclyl”, and “substituted carbocyclyl”means alkyl, alkylene, aryl, arylalkyl, heterocyclyl, carbocyclylrespectively, in which one or more hydrogen atoms are each independentlyreplaced with a non-hydrogen substituent. Typical substituents include,but are not limited to, —X, —R, —O—, ═O, —OR, —SR, —S—, —NR₂, —N⁺R₃,═NR, —CX₃, —CN, —OCN, —SCN, —N═C═O, —NCS, —NO, —NO₂, ═N₂, —N₃,—NHC(═O)R, —NHS(═O)₂R, —C(═O)R, —C(═O)NRR—S(═O)₂O⁻, —S(═O)₂OH, —S(═O)₂R,—OS(═O)₂OR, —S(═O)₂NR, —S(═O)R, —OP(═O)(OR)₂, —P(═O)(OR)₂, —P(═O)(O⁻)₂,—P(═O)(OH)₂, —P(O)(OR)(O⁻), —C(═O)R, —C(═O)OR, —C(═O)X, —C(S)R, —C(O)OR,—C(O)O⁻, —C(S)OR, —C(O)SR, —C(S)SR, —C(O)NRR, —C(S)NRR, —C(═NR)NRR,where each X is independently a halogen: F, Cl, Br, or I; and each R isindependently H, alkyl, aryl, arylalkyl, a heterocycle, or a protectinggroup or prodrug moiety. Alkylene, alkenylene, and alkynylene groups mayalso be similarly substituted. When the number of carbon atoms isdesignated for a substituted group, the number of carbon atoms refers tothe group, not the substituent (unless otherwise indicated). Forexample, a C₁₋₄ substituted alkyl refers to a C₁₋₄ alkyl, which can besubstituted with groups having more the, e.g., 4 carbon atoms.

The term “prodrug” as used herein refers to any compound that whenadministered to a biological system generates the drug substance, i.e.,active ingredient, as a result of spontaneous chemical reaction(s),enzyme catalyzed chemical reaction(s), photolysis, and/or metabolicchemical reaction(s). A prodrug is thus a covalently modified analog orlatent form of a therapeutically active compound.

One skilled in the art will recognize that substituents and othermoieties of the compounds of Formula I should be selected in order toprovide a compound which is sufficiently stable to provide apharmaceutically useful compound which can be formulated into anacceptably stable pharmaceutical composition. Compounds of Formula Iwhich have such stability are contemplated as falling within the scopeof the present invention.

“Heteroalkyl” refers to an alkyl group where one or more carbon atomshave been replaced with a heteroatom, such as, O, N, or S. For example,if the carbon atom of the alkyl group which is attached to the parentmolecule is replaced with a heteroatom (e.g., O, N, or S) the resultingheteroalkyl groups are, respectively, an alkoxy group (e.g., —OCH₃,etc.), an amine (e.g., —NHCH₃, —N(CH₃)₂, etc.), or a thioalkyl group(e.g., —SCH₃). If a non-terminal carbon atom of the alkyl group which isnot attached to the parent molecule is replaced with a heteroatom (e.g.,O, N, or S) the resulting heteroalkyl groups are, respectively, an alkylether (e.g., —CH₂CH₂—O—CH₃, etc.), an alkyl amine (e.g., —CH₂NHCH₃,—CH₂N(CH₃)₂, etc.), or a thioalkyl ether (e.g., —CH₂—S—CH₃). If aterminal carbon atom of the alkyl group is replaced with a heteroatom(e.g., O, N, or S), the resulting heteroalkyl groups are, respectively,a hydroxyalkyl group (e.g., —CH₂CH₂—OH), an aminoalkyl group (e.g.,—CH₂NH₂), or an alkyl thiol group (e.g., —CH₂CH₂—SH). A heteroalkylgroup can have, for example, 1 to 20 carbon atoms, 1 to 10 carbon atoms,or 1 to 6 carbon atoms. A C₁-C₆ heteroalkyl group means a heteroalkylgroup having 1 to 6 carbon atoms.

“Heterocycle” or “heterocyclyl” as used herein includes by way ofexample and not limitation those heterocycles described in Paquette, LeoA.; Principles of Modern Heterocyclic Chemistry (W. A. Benjamin, NewYork, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; The Chemistryof Heterocyclic Compounds, A Series of Monographs” (John Wiley & Sons,New York, 1950 to present), in particular Volumes 13, 14, 16, 19, and28; and J. Am. Chem. Soc. (1960) 82:5566. In one specific embodiment ofthe invention “heterocycle” includes a “carbocycle” as defined herein,wherein one or more (e.g. 1, 2, 3, or 4) carbon atoms have been replacedwith a heteroatom (e.g. O, N, or S). The terms “heterocycle” or“heterocyclyl” includes saturated rings, partially unsaturated rings,and aromatic rings (i.e., heteroaromatic rings). Substitutedheterocyclyls include, for example, heterocyclic rings substituted withany of the substituents disclosed herein including carbonyl groups. Anon-limiting example of a carbonyl substituted heterocyclyl is:

Examples of heterocycles include by way of example and not limitationpyridyl, dihydroypyridyl, tetrahydropyridyl (piperidyl), thiazolyl,tetrahydrothiophenyl, sulfur oxidized tetrahydrothiophenyl, pyrimidinyl,furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl,benzofuranyl, thianaphthalenyl, indolyl, indolenyl, quinolinyl,isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl,2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroisoquinolinyl,azocinyl, triazinyl, 6H-1,2,5-thiadiazinyl, 2H,6H-1,5,2-dithiazinyl,thienyl, thianthrenyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl,phenoxathinyl, 2H-pyrrolyl, isothiazolyl, isoxazolyl, pyrazinyl,pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, 1H-indazoly, purinyl,4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl,quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl,β-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl,chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl pyrazolinyl,piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl,oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl,isatinoyl, and bis-tetrahydrofuranyl:

By way of example and not limitation, carbon bonded heterocycles arebonded at position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5, or6 of a pyridazine, position 2, 4, 5, or 6 of a pyrimidine, position 2,3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan,tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole,position 2, 4, or 5 of an oxazole, imidazole or thiazole, position 3, 4,or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of anaziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6,7, or 8 of a quinoline or position 1, 3, 4, 5, 6, 7, or 8 of anisoquinoline. Still more typically, carbon bonded heterocycles include2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl,4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl,4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl,5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, or 5-thiazolyl.

By way of example and not limitation, nitrogen bonded heterocycles arebonded at position 1 of an aziridine, azetidine, pyrrole, pyrrolidine,2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline,3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline,piperidine, piperazine, indole, indoline, 1H-indazole, position 2 of aisoindole, or isoindoline, position 4 of a morpholine, and position 9 ofa carbazole, or β-carboline. Still more typically, nitrogen bondedheterocycles include 1-aziridyl, 1-azetedyl, 1-pyrrolyl, 1-imidazolyl,1-pyrazolyl, and 1-piperidinyl.

“Heterocyclylalkyl” refers to an acyclic alkyl radical in which one ofthe hydrogen atoms bonded to a carbon atom, typically a terminal or sp³carbon atom, is replaced with a heterocyclyl radical (i.e., aheterocyclyl-alkylene-moiety). Typical heterocyclyl alkyl groupsinclude, but are not limited to heterocyclyl-CH₂—,heterocyclyl-CH(CH₃)—, heterocyclyl-CH₂CH₂—, 2-(heterocyclyl)ethan-1-yl,and the like, wherein the “heterocyclyl” portion includes any of theheterocyclyl groups described above, including those described inPrinciples of Modern Heterocyclic Chemistry. One skilled in the art willalso understand that the heterocyclyl group can be attached to the alkylportion of the heterocyclyl alkyl by means of a carbon-carbon bond or acarbon-heteroatom bond, with the proviso that the resulting group ischemically stable. The heterocyclylalkyl group comprises 2 to 20 carbonatoms, e.g., the alkyl portion of the heterocyclylalkyl group is 1 to 6carbon atoms and the heterocyclyl moiety is 1 to 14 carbon atoms.Examples of heterocyclylalkyls include by way of example and notlimitation 5-membered sulfur, oxygen, and/or nitrogen containingheterocycles such as thiazolylmethyl, 2-thiazolylethan-1-yl,imidazolylmethyl, oxazolylmethyl, thiadiazolylmethyl, etc., 6-memberedsulfur, oxygen, and/or nitrogen containing heterocycles such aspiperidinylmethyl, piperazinylmethyl, morpholinylmethyl,pyridinylmethyl, pyridizylmethyl, pyrimidylmethyl, pyrazinylmethyl, etc.

“Heterocyclylalkenyl” refers to an acyclic alkenyl radical in which oneof the hydrogen atoms bonded to a carbon atom, typically a terminal orsp³ carbon atom, but also a sp² carbon atom, is replaced with aheterocyclyl radical (i.e., a heterocyclyl-alkenylene-moiety). Theheterocyclyl portion of the heterocyclyl alkenyl group includes any ofthe heterocyclyl groups described herein, including those described inPrinciples of Modern Heterocyclic Chemistry, and the alkenyl portion ofthe heterocyclyl alkenyl group includes any of the alkenyl groupsdisclosed herein. One skilled in the art will also understand that theheterocyclyl group can be attached to the alkenyl portion of theheterocyclyl alkenyl by means of a carbon-carbon bond or acarbon-heteroatom bond, with the proviso that the resulting group ischemically stable. The heterocyclylalkenyl group comprises 3 to 20carbon atoms, e.g., the alkenyl portion of the heterocyclyl alkenylgroup is 2 to 6 carbon atoms and the heterocyclyl moiety is 1 to 14carbon atoms.

“Heterocyclylalkynyl” refers to an acyclic alkynyl radical in which oneof the hydrogen atoms bonded to a carbon atom, typically a terminal orsp³ carbon atom, but also an sp carbon atom, is replaced with aheterocyclyl radical (i.e., a heterocyclyl-alkynylene-moiety). Theheterocyclyl portion of the heterocyclyl alkynyl group includes any ofthe heterocyclyl groups described herein, including those described inPrinciples of Modern Heterocyclic Chemistry, and the alkynyl portion ofthe heterocyclyl alkynyl group includes any of the alkynyl groupsdisclosed herein. One skilled in the art will also understand that theheterocyclyl group can be attached to the alkynyl portion of theheterocyclyl alkynyl by means of a carbon-carbon bond or acarbon-heteroatom bond, with the proviso that the resulting group ischemically stable. The heterocyclylalkynyl group comprises 3 to 20carbon atoms, e.g., the alkynyl portion of the heterocyclylalkynyl groupis 2 to 6 carbon atoms and the heterocyclyl moiety is 1 to 14 carbonatoms.

“Heteroaryl” refers to an aromatic heterocyclyl having at least oneheteroatom in the ring. Non-limiting examples of suitable heteroatomswhich can be included in the aromatic ring include oxygen, sulfur, andnitrogen. Non-limiting examples of heteroaryl rings include all of thoselisted in the definition of “heterocyclyl”, including pyridinyl,pyrrolyl, oxazolyl, indolyl, isoindolyl, purinyl, furanyl, thienyl,benzofuranyl, benzothiophenyl, carbazolyl, imidazolyl, thiazolyl,isoxazolyl, pyrazolyl, isothiazolyl, quinolyl, isoquinolyl, pyridazyl,pyrimidyl, pyrazyl, etc.

“Carbocycle” or “carbocyclyl” refers to a saturated (i.e., cycloalkyl),partially unsaturated (e.g., cycloakenyl, cycloalkadienyl, etc.) oraromatic ring having 3 to 7 carbon atoms as a monocycle, 7 to 12 carbonatoms as a bicycle, and up to about 20 carbon atoms as a polycycle.Monocyclic carbocycles have 3 to 6 ring atoms, still more typically 5 or6 ring atoms. Bicyclic carbocycles have 7 to 12 ring atoms, e.g.,arranged as a bicyclo[4,5], [5,5], [5,6] or [6,6] system, or 9 or 10ring atoms arranged as a bicyclo[5,6] or [6,6] system, or spiro-fusedrings. Non-limiting examples of monocyclic carbocycles includecyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl,1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl,1-cyclohex-2-enyl, 1-cyclohex-3-enyl, and phenyl. Non-limiting examplesof bicyclo carbocycles includes naphthyl.

“Arylheteroalkyl” refers to a heteroalkyl as defined herein, in which ahydrogen atom (which may be attached either to a carbon atom or aheteroatom) has been replaced with an aryl group as defined herein. Thearyl groups may be bonded to a carbon atom of the heteroalkyl group, orto a heteroatom of the heteroalkyl group, provided that the resultingarylheteroalkyl group provides a chemically stable moiety. For example,an arylheteroalkyl group can have the general formulae -alkylene-O-aryl,-alkylene-O-alkylene-aryl, -alkylene-NH-aryl,-alkylene-NH-alkylene-aryl, -alkylene-5-aryl, -alkylene-5-alkylene-aryl,etc. In addition, any of the alkylene moieties in the general formulaeabove can be further substituted with any of the substituents defined orexemplified herein.

“Heteroarylalkyl” refers to an alkyl group, as defined herein, in whicha hydrogen atom has been replaced with a heteroaryl group as definedherein. Non-limiting examples of heteroaryl alkyl include—CH₂-pyridinyl, —CH₂-pyrrolyl, —CH₂-oxazolyl, —CH₂-indolyl,—CH₂-isoindolyl, —CH₂-purinyl, —CH₂-furanyl, —CH₂-thienyl,—CH₂-benzofuranyl, —CH₂-benzothiophenyl, —CH₂-carbazolyl,—CH₂-imidazolyl, —CH₂-thiazolyl, —CH₂-isoxazolyl, —CH₂-pyrazolyl,—CH₂-isothiazolyl, —CH₂-quinolyl, —CH₂-isoquinolyl, —CH₂-pyridazyl,—CH₂-pyrimidyl, —CH₂-pyrazyl, —CH(CH₃)-pyridinyl, —CH(CH₃)-pyrrolyl,—CH(CH₃)-oxazolyl, —CH(CH₃)-indolyl, —CH(CH₃)-isoindolyl,—CH(CH₃)-purinyl, —CH(CH₃)-furanyl, —CH(CH₃)-thienyl,—CH(CH₃)-benzofuranyl, —CH(CH₃)-benzothiophenyl, —CH(CH₃)-carbazolyl,—CH(CH₃)-imidazolyl, —CH(CH₃)-thiazolyl, —CH(CH₃)-isoxazolyl,—CH(CH₃)-pyrazolyl, —CH(CH₃)-isothiazolyl, —CH(CH₃)-quinolyl,—CH(CH₃)-isoquinolyl, —CH(CH₃)-pyridazyl, —CH(CH₃)-pyrimidyl,—CH(CH₃)-pyrazyl, etc.

The term “optionally substituted” in reference to a particular moiety ofthe compound of Formula I (e.g., an optionally substituted aryl group)refers to a moiety having 0, 1, 2, or more substituents.

“Ac” means acetyl (—C(O)CH₃).

“Ac₂O” means acetic anhydride.

“DCM” means dichloromethane (CH₂Cl₂).

“DIBAL” means diisobutylaluminum hydride.

“DMAP” means dimethylaminopyridine.

“EDC” means 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide.

“Et” means ethyl.

“EtOAc” means ethylacetate.

“HOBt” means N-hydroxybenzotriazole.

“Me” means methyl (—CH₃).

“MeOH” means methanol.

“MeCN” means acetonitrile.

“Pr” means propyl.

“i-Pr” means isopropyl (—CH(CH₃)₂).

“i-PrOH” means isopropanol.

“rt” means room temperature.

“TFA” means trifluoroacetic acid.

“THF” means tetrahydrofuran.

The term “chiral” refers to molecules which have the property ofnon-superimposability of the mirror image partner, while the term“achiral” refers to molecules which are superimposable on their mirrorimage partner.

The term “stereoisomers” refers to compounds which have identicalchemical constitution, but differ with regard to the arrangement of theatoms or groups in space.

“Diastereomer” refers to a stereoisomer with two or more centers ofchirality and whose molecules are not mirror images of one another.Diastereomers have different physical properties, e.g., melting points,boiling points, spectral properties, and reactivities. Mixtures ofdiastereomers may separate under high resolution analytical proceduressuch as electrophoresis and chromatography.

“Enantiomers” refer to two stereoisomers of a compound which arenon-superimposable mirror images of one another.

Stereochemical definitions and conventions used herein generally followS. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984)McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S.,Stereochemistry of Organic Compounds (1994) John Wiley & Sons, Inc., NewYork. Many organic compounds exist in optically active forms, i.e., theyhave the ability to rotate the plane of plane-polarized light. Indescribing an optically active compound, the prefixes D and L or R and Sare used to denote the absolute configuration of the molecule about itschiral center(s). The prefixes d and l or (+) and (−) are employed todesignate the sign of rotation of plane-polarized light by the compound,with (−) or 1 meaning that the compound is levorotatory. A compoundprefixed with (+) or d is dextrorotatory. For a given chemicalstructure, these stereoisomers are identical except that they are mirrorimages of one another. A specific stereoisomer may also be referred toas an enantiomer, and a mixture of such isomers is often called anenantiomeric mixture. A 50:50 mixture of enantiomers is referred to as aracemic mixture or a racemate, which may occur where there has been nostereoselection or stereospecificity in a chemical reaction or process.The terms “racemic mixture” and “racemate” refer to an equimolar mixtureof two enantiomeric species, devoid of optical activity.

Protecting Groups

In the context of the present invention, protecting groups includeprodrug moieties and chemical protecting groups.

Protecting groups are available, commonly known and used, and areoptionally used to prevent side reactions with the protected groupduring synthetic procedures, i.e. routes or methods to prepare thecompounds of the invention. For the most part the decision as to whichgroups to protect, when to do so, and the nature of the chemicalprotecting group “PG” will be dependent upon the chemistry of thereaction to be protected against (e.g., acidic, basic, oxidative,reductive or other conditions) and the intended direction of thesynthesis. The PG groups do not need to be, and generally are not, thesame if the compound is substituted with multiple PG. In general, PGwill be used to protect functional groups such as carboxyl, hydroxyl,thio, or amino groups and to thus prevent side reactions or to otherwisefacilitate the synthetic efficiency. The order of deprotection to yieldfree, deprotected groups is dependent upon the intended direction of thesynthesis and the reaction conditions to be encountered, and may occurin any order as determined by the artisan.

Various functional groups of the compounds of the invention may beprotected. For example, protecting groups for —OH groups (whetherhydroxyl, carboxylic acid, phosphonic acid, or other functions) include“ether- or ester-forming groups”. Ether- or ester-forming groups arecapable of functioning as chemical protecting groups in the syntheticschemes set forth herein. However, some hydroxyl and thio protectinggroups are neither ether- nor ester-forming groups, as will beunderstood by those skilled in the art, and are included with amides,discussed below.

A very large number of hydroxyl protecting groups and amide-forminggroups and corresponding chemical cleavage reactions are described inProtective Groups in Organic Synthesis, Theodora W. Greene and Peter G.M. Wuts (John Wiley & Sons, Inc., New York, 1999, ISBN 0-471-16019-9)(“Greene”). See also Kocienski, Philip J.; Protecting Groups (GeorgThieme Verlag Stuttgart, New York, 1994), which is incorporated byreference in its entirety herein. In particular Chapter 1, ProtectingGroups: An Overview, pages 1-20, Chapter 2, Hydroxyl Protecting Groups,pages 21-94, Chapter 3, Diol Protecting Groups, pages 95-117, Chapter 4,Carboxyl Protecting Groups, pages 118-154, Chapter 5, CarbonylProtecting Groups, pages 155-184. For protecting groups for carboxylicacid, phosphonic acid, phosphonate, sulfonic acid and other protectinggroups for acids see Greene as set forth below. Such groups include byway of example and not limitation, esters, amides, hydrazides, and thelike.

Ether- and Ester-Forming Protecting Groups

Ester-forming groups include: (1) phosphonate ester-forming groups, suchas phosphonamidate esters, phosphorothioate esters, phosphonate esters,and phosphon-bis-amidates; (2) carboxyl ester-forming groups, and (3)sulphur ester-forming groups, such as sulphonate, sulfate, andsulfinate.

Metabolites of the Compounds of the Invention

Also falling within the scope of this invention are the in vivometabolic products of the compounds described herein. Such products mayresult for example from the oxidation, reduction, hydrolysis, amidation,esterification and the like of the administered compound, primarily dueto enzymatic processes. Accordingly, the invention includes compoundsproduced by a process comprising contacting a compound of this inventionwith a mammal for a period of time sufficient to yield a metabolicproduct thereof. Such products typically are identified by preparing aradiolabelled (e.g., C¹⁴ or H³) compound of the invention, administeringit parenterally in a detectable dose (e.g., greater than about 0.5mg/kg) to an animal such as rat, mouse, guinea pig, monkey, or to man,allowing sufficient time for metabolism to occur (typically about 30seconds to 30 hours) and isolating its conversion products from theurine, blood or other biological samples. These products are easilyisolated since they are labeled (others are isolated by the use ofantibodies capable of binding epitopes surviving in the metabolite). Themetabolite structures are determined in conventional fashion, e.g., byMS or NMR analysis. In general, analysis of metabolites is done in thesame way as conventional drug metabolism studies well-known to thoseskilled in the art. The conversion products, so long as they are nototherwise found in vivo, are useful in diagnostic assays for therapeuticdosing of the compounds of the invention even if they possess noanti-infective activity of their own.

Compounds of Formula I

In one embodiment, the present application provides compounds accordingto Formula I, as described herein.

In another embodiment of the compounds of Formula I, n is 1.

In another embodiment of the compounds of Formula I, n is 0.

In another embodiment of the compounds of Formula I, n is 1 and L² is—CH(R⁶)—, wherein R⁶ is selected from the group consisting of H, alkyl,substituted alkyl, and heteroalkyl.

In another embodiment of the compounds of Formula I, n is 1 and L² is—CH₂—.

In another embodiment of the compounds of Formula I, n is 1 and L² is—C(O)—.

In another embodiment of the compounds of Formula I, n is 1 and Y isheterocyclylalkyl.

In another embodiment of the compounds of Formula I, n is 1 and Y—R⁸ is—CH₂-(substituted heteroaryl).

In another embodiment of the compounds of Formula I, n is 1 and Y—R⁸ is

In another embodiment of the compounds of Formula I, n is 1 and Y—R⁸ is

wherein R⁸ is alkyl, for example 2-propyl.

In another embodiment of the compounds of Formula I, n is 1 and X isheterocyclylalkyl.

In another embodiment of the compounds of Formula I, n is 1 and X is—CH₂-heteroaryl.

In another embodiment of the compounds of Formula I, n is 1 and X—R⁹ is

In another embodiment of the compounds of Formula I, n is 1 and X—R⁹ is

In another embodiment of the compounds of Formula I, n is 1 and Z¹ is—N(R⁷)—.

In another embodiment of the compounds of Formula I, n is 1 and Z, is—N(alkyl)- or —N(carbocyclyl)-.

In another embodiment of the compounds of Formula I, n is 1 and Z¹ is—N(CH₃)— or —N(cyclopropyl)-.

In another embodiment of the compounds of Formula I, n is 1 and Z¹ is—NH—.

In another embodiment of the compounds of Formula I, n is 1 and each Ais independently aryl or substituted aryl.

In another embodiment of the compounds of Formula I, n is 1 and each Ais phenyl.

In another embodiment of the compounds of Formula I, n is 1 and each Ais phenyl and each p is 0.

In another embodiment of the compounds of Formula I, n is 1 and R² is H,alkyl, substituted alkyl, or heteroalkyl.

In another embodiment of the compounds of Formula I, n is 1 and R² is2-propyl, methyl, —CH₂—O-benzyl, —CH(CH₃)(O-t-Bu), or —CH(CH₃)(OH).

In another embodiment of the compounds of Formula I, L¹ is —C(O)—;

-   -   each A is independently aryl, substituted aryl, alkyl, or        substituted alkyl;    -   R¹ is H or alkyl;    -   each R² is independently H, alkyl, substituted alkyl, or        heteroalkyl;    -   R³, R⁴, R⁵, and R⁶ are each H;    -   each R⁷ is independently H, alkyl, or carbocyclyl;    -   R⁸ is H or alkyl;    -   R⁹ is H;    -   X and Y are both heterocyclylalkyl;    -   Z² is —O—; and    -   p is 0.

In another embodiment of the compounds of Formula I, each A is phenyl;

-   -   R¹ is H or —CH₃;    -   each R² is H, methyl, ethyl, 2-propyl, —CH₂—O-benzyl,        —CH(CH₃)—OH, or —CH(CH₃)(O-t-Bu);    -   each R⁷ is H, methyl or cyclopropyl;    -   R⁸ is H or 2-propyl;    -   X is

In another embodiment, the compounds of Formula I have the followinggeneral Formula IA:

In another embodiment of the compounds of Formula IA, Z¹ is —N(R⁷)—. Ina particular embodiment, R⁷ is H. In another particular embodiment, R⁷is alkyl, for example any of the alkyl groups disclosed herein. Inanother particular embodiment, R⁷ is heteroalkyl, for example any of theheteroalkyl groups disclosed herein. In another particular embodiment,R⁷ is substituted or unsubstituted carbocyclyl, wherein for example,said carbocyclyl is any of the carbocyclyl groups disclosed herein. Inanother particular embodiment, R⁷ is substituted or unsubstitutedheterocyclyl, wherein for example, said heterocyclyl is any of theheterocyclyl groups disclosed herein.

In another embodiment of the compounds of Formula IA, Z¹ is —O—.

In another embodiment of the compounds of Formula IA, L² is —C(R⁶)₂—,wherein each R⁶ is H.

In another embodiment of the compounds of Formula IA, L² is —C(R⁶)₂—,wherein each R⁶ is independently H or alkyl, and said alkyl includes anyalkyl disclosed herein.

In another embodiment of the compounds of Formula IA, L² is —C(R⁶)₂—,wherein one R⁶ is H and the other R⁶ is alkyl, wherein said alkylincludes any alkyl disclosed herein.

In another embodiment of the compounds of Formula IA, m is 1 and R² isH.

In another embodiment of the compounds of Formula IA, m is 1 and R² isalkyl, wherein said alkyl includes any alkyl disclosed herein.

In another embodiment of the compounds of Formula IA, m is 1 and R² isi-propyl.

In another embodiment of the compounds of Formula IA, m is 1 and R² isi-butyl.

In another embodiment of the compounds of Formula IA, m is 1 and R² isethyl.

In another embodiment of the compounds of Formula IA, m is 1 and R² ismethyl.

In another embodiment of the compounds of Formula IA, m is 2 and each R²is independently selected from H and alkyl.

In another embodiment of the compounds of Formula IA, m is 2 and each R²is H.

In another embodiment, the compounds of Formula I have the followinggeneral Formula IB:

In another embodiment of the compounds of Formula IB, Z¹ is —N(R⁷)—. Ina particular embodiment, R⁷ is H. In another particular embodiment, R⁷is alkyl, for example any of the alkyl groups disclosed herein. Inanother particular embodiment, R⁷ is heteroalkyl, for example any of theheteroalkyl groups disclosed herein. In another particular embodiment,R⁷ is substituted or unsubstituted carbocyclyl, wherein for example,said carbocyclyl is any of the carbocyclyl groups disclosed herein. Inanother particular embodiment, R⁷ is substituted or unsubstitutedheterocyclyl, wherein for example, said heterocyclyl is any of theheterocyclyl groups disclosed herein.

In another embodiment of the compounds of Formula IB, Z¹ is —O—.

In another embodiment of the compounds of Formula IB, L² is —C(R⁶)₂—,wherein each R⁶ is H.

In another embodiment of the compounds of Formula IB, L² is —C(R⁶)₂—,wherein each R⁶ is independently H or alkyl, and said alkyl includes anyalkyl disclosed herein.

In another embodiment of the compounds of Formula IB, L² is —C(R⁶)₂—,wherein one R⁶ is H and the other R⁶ is alkyl, wherein said alkylincludes any alkyl disclosed herein.

In another embodiment of the compounds of Formula IB, R⁸ and R⁹ are bothH.

In another embodiment of the compounds of Formula IB, R⁸ and R⁹ areindependently selected from H and alkyl, wherein said alkyl includes anyalkyl disclosed herein.

In another embodiment, the compounds of Formula I have one of thefollowing structures:

including stereoisomers or mixtures of stereoisomers thereof. Oneskilled in the art will recognize that stereoisomers or mixtures ofstereoisomers of the compounds of the present application includeenantiomers, diastereomers, and other stereoisomers. For example, for:

contemplated stereoisomers include at least:

as well as mixtures of two or more of these stereoisomers.

In still another embodiment of the compounds of Formula I, L¹ is—C(R⁶)₂—, —C(O)—, —S(O₂)—, —N(R⁷)—C(O)—, or —O—C(O)—. When L¹ is—C(R⁶)₂—, each R⁶ is independently selected from the group consisting ofH, alkyl, substituted alkyl, and heteroalkyl, wherein alkyl, substitutedalkyl, and heteroalkyl are as defined and exemplified herein.Non-limiting examples of —C(R⁶)₂— include —CH₂—, —CH(alkyl)-,—CH(substituted alkyl)-, —CH(heteroalkyl)-, —C(alkyl)₂-, —C(substitutedalkyl)₂-, —C(heteroalkyl)₂-, —C(alkyl)(substituted alkyl)-,—C(heteroalkyl)(substituted alkyl)-, and —C(alkyl)(heteroalkyl)-,wherein alkyl, substituted alkyl, and heteroalkyl are as defined andexemplified herein. When L¹ is —N(R⁷)—C(O)—, R⁷ is H, alkyl, substitutedalkyl, heteroalkyl, carbocyclyl, substituted carbocyclyl, heterocyclyl,or substituted heterocyclyl, wherein alkyl, substituted alkyl,heteroalkyl, carbocyclyl, substituted carbocyclyl, heterocyclyl, orsubstituted heterocyclyl are as defined and exemplified herein.

In still another embodiment of the compounds of Formula I, L² is—C(R⁶)₂— or —C(O)—. When L² is —C(R⁶)₂—, each R⁶ is independentlyselected from H, alkyl, substituted alkyl or heteroalkyl, where eachalkyl, substituted alkyl, or heteroalkyl can include any of the alkyl,substituted alkyl, or heteroalkyl groups defined or disclosed herein.Non-limiting examples of —C(R⁶)₂— include —CH₂—, —CH(CH₃)—,—CH(—CH₂CH₃)—, —CH(—CH₂CH₂CH₃)—, —CH(—CH(CH₃)₂)—, —CH(—CH₂CH₂CH₂CH₃)—,—CH(—CH₂CH(CH₃)₂)—, —CH(—CH(CH₃)CH₂CH₃)—, —CH(—C(CH₃)₃)—, —C(CH₃)₂—,—CH(OCH₃)—, —CH(CH₂OH)—, —CH(CH₂CH₂OH)—, etc.

In still another embodiment of the compounds of Formula I, each L³ isindependently a covalent bond, an alkylene or substituted alkylene. Whenany L³ is an alkylene, non-limiting examples of alkylene includes any ofthe alkylenes defined or disclosed herein. When any L³ is a substitutedalkylene, non-limiting examples of substituted alkylene includes any ofthe substituted alkylenes defined or disclosed herein. For example,substituted alkylenes include alkylenes substituted with one or more —OHgroup, alkylenes substituted with one or more ether group, e.g., a —O-Bngroup, alkylenes substituted with one or more halogen, or alkylenessubstituted with combinations of two or more substituents (e.g., —OH andhalogen, halogen and ether, etc.).

In still another embodiment of the compounds of Formula I, each L³ isthe same, i.e., each L³ is the same alkylene or substituted alkylenegroup.

In still another embodiment of the compounds of Formula I, each L³ isdifferent, i.e., one L³ is an alkylene and the other L³ is a substitutedalkylene, one L³ is an alkylene and the other L³ is a differentalkylene, or one L³ is a substituted alkylene, and the other L³ is adifferent substituted alkylene.

In still another embodiment of the compounds of Formula I, each L⁴ isindependently selected from the group consisting of a covalent bond,alkylene, substituted alkylene, —O—, —CH₂—O—, and —NH—. When L⁴ isalkylene, said alkylene includes any alkylene defined or exemplifiedherein. When L⁴ is substituted alkylene, said substituent includes anyalkylene defined or exemplified herein, substituted by one or moresubstituents as defined herein.

In still another embodiment of the compounds of Formula I, both L⁴groups are the same, i.e. both L⁴ groups are a covalent bond, both are—O—, both are —CH₂—O—, (wherein the CH₂ group is attached to either the“A” moiety or the “Ar” moiety of Formula I), both are a substituted orunsubstituted alkylene, or both are —NH—.

In still another embodiment of the compounds of Formula I, each L⁴ isdifferent. For example, one L⁴ is a covalent bond and the other L⁴ is—O—, one L⁴ is a covalent bond and the other L⁴ is —CH₂—O— (wherein theCH₂ group is attached to either the “A” moiety or the “Ar” moiety ofFormula I), one L⁴ is a covalent bond and the other L⁴ is —NH—, one L⁴is a —O— and the other L⁴ is —CH₂—O— (wherein the CH₂ group is attachedto either the “A” moiety or the “Ar” moiety of Formula I), one L⁴ is —O—and the other L⁴ is —NH—, one L⁴ is —CH₂—O— (wherein the CH₂ group isattached to either the “A” moiety or the “Ar” moiety of Formula I) andthe other L⁴ is —NH—, one L4 is a covalent bond and the other L⁴ is asubstituted or unsubstituted alkylene, one L⁴ is a substituted alkyleneand the other L⁴ is a unsubstituted alkylene, one L⁴ is a substituted orunsubstituted alkene and the other L⁴ is —O—, one L⁴ is a substituted orunsubstituted alkylene and the other L⁴ is —CH₂—O— (wherein the CH₂group is attached to either the “A” moiety or the “Ar” moiety of FormulaI), or one L⁴ is substituted or unsubstituted alkylene and the other L⁴is —NH—.

In still another embodiment of the compounds of Formula I, each A isindependently H, alkyl, substituted alkyl, aryl, substituted aryl,heterocyclyl, or substituted heterocyclyl, with the proviso that when Ais H, p is 0. When any A is alkyl, said alkyl includes any alkyl definedor exemplified herein. When any A is substituted alkyl, said alkylincludes any alkyl defined or exemplified herein substituted with one ormore of any substituent defined or exemplified herein. When any A isaryl, said aryl includes any aryl defined or exemplified herein. Whenany A is substituted aryl, said aryl includes any aryl defined orexemplified herein substituted with one or more of any substituentdefined or exemplified herein. When any A is heterocyclyl, saidheterocyclyl includes any heterocyclyl defined or exemplified herein.When any A is substituted heterocyclyl, said heterocyclyl is anyheterocyclyl defined or exemplified herein substituted with one or moreof any substituent defined or exemplified herein.

In still another embodiment of the compounds of Formula I, each A is Hand each p is 0.

In still another embodiment of the compounds of Formula I, each A issubstituted or unsubstituted alkyl, wherein alkyl is any alkyl definedor exemplified herein, and, when present, the substituents on said alkylinclude one or more of any substituents defined or exemplified herein.

In still another embodiment of the compounds of Formula I, each A issubstituted or unsubstituted aryl, wherein aryl is any aryl defined orexemplified herein, and, when present, the substituents on said arylinclude one or more of any substituents defined or exemplified herein.In a particular embodiment, A is phenyl.

In still another embodiment of the compounds of Formula I, each A issubstituted or unsubstituted heterocyclyl, wherein heterocyclyl is anyheterocyclyl defined or exemplified herein, and, when present, thesubstituents on said heterocyclyl include one or more of anysubstituents defined or exemplified herein.

In still another embodiment of the compounds of Formula I, one A is Hand the other A is substituted or unsubstituted alkyl, wherein alkyl isany alkyl defined or exemplified herein, and, when present, thesubstituent on said alkyl includes one or more of any substituentdefined or exemplified herein.

In still another embodiment of the compounds of Formula I, one A is Hand the other A is substituted or unsubstituted aryl, wherein aryl isany aryl defined or exemplified herein, and the substituents on saidaryl are any substituents defined and exemplified herein. In aparticular embodiment, one A is phenyl.

In still another embodiment of the compounds of Formula I, one A is Hand the other A is substituted or unsubstituted heterocyclyl, whereinheterocyclyl is any heterocyclyl defined or exemplified herein, and,when present, the substituents on said heterocyclyl include one or moreof any substituent defined or exemplified herein.

In still another embodiment of the compounds of Formula I, one A issubstituted or unsubstituted alkyl, and the other A is substituted orunsubstituted aryl, wherein alkyl and aryl are any alkyl or aryl definedor exemplified herein, and, when present, the substituents on said alkylor aryl include one or more of any substituents defined or exemplifiedherein.

In still another embodiment of the compounds of Formula I, one A issubstituted or unsubstituted alkyl, and the other A is substituted orunsubstituted heterocyclyl, wherein alkyl and heterocyclyl are any alkylor heterocyclyl defined or exemplified herein, and, when present, thesubstituents on said alkyl or heterocyclyl include one or more of anysubstituents defined or exemplified herein.

In still another embodiment of the compounds of Formula I, one A issubstituted or unsubstituted aryl, and the other A is substituted orunsubstituted heterocyclyl, wherein aryl and heterocyclyl are any arylor heterocyclyl defined or exemplified herein, and, when present, thesubstituents on said aryl or heterocyclyl include one or more of anysubstituents defined or exemplified herein.

In still another embodiment of the compounds of Formula I, Z¹ is —O— or—N(R⁷)—. When Z¹ is —N(R⁷)—, R⁷ is H, alkyl, substituted alkyl,heteroalkyl, carbocyclyl, substituted carbocyclyl, heterocyclyl, orsubstituted heterocyclyl, wherein alkyl, substituted alkyl, heteroalkyl,carbocyclyl, substituted carbocyclyl, heterocyclyl, or substitutedheterocyclyl are any alkyl, substituted alkyl, heteroalkyl, carbocyclyl,substituted carbocyclyl, heterocyclyl, or substituted heterocyclyldefined or exemplified herein.

In still another embodiment of the compounds of Formula I, Z² is —O— or—N(R⁷)—. When Z² is —N(R⁷)—, R⁷ is H, alkyl, substituted alkyl,heteroalkyl, carbocyclyl, substituted carbocyclyl, heterocyclyl, orsubstituted heterocyclyl, wherein alkyl, substituted alkyl, heteroalkylcarbocyclyl, substituted carbocyclyl, heterocyclyl, or substitutedheterocyclyl are any alkyl, substituted alkyl, heteroalkyl, carbocyclyl,substituted carbocyclyl, heterocyclyl, or substituted heterocyclyldefined or exemplified herein.

In still another embodiment of the compounds of Formula I, Z¹ and Z² arethe same, e.g., Z¹ and Z² are both —O—, or Z¹ and Z² are both —N(R⁷)—,where R⁷ is H, alkyl, substituted alkyl, heteroalkyl, carbocyclyl,substituted carbocyclyl, heterocyclyl, or substituted heterocyclyl,wherein alkyl, substituted alkyl, heteroalkyl, carbocyclyl, substitutedcarbocyclyl, heterocyclyl, or substituted heterocyclyl are any alkyl,substituted alkyl, heteroalkyl, carbocyclyl, substituted carbocyclyl,heterocyclyl, or substituted heterocyclyl defined or exemplified herein.

In still another embodiment of the compounds of Formula I, Z¹ and Z² aredifferent, e.g. Z¹ is —O— and Z² is —N(R⁷)—, Z¹ is —N(R⁷)— and Z² is—O—, or Z¹ and Z² are both —N(R⁷)— but in Z¹ the R⁷ is different fromthe R⁷ in Z². When either Z¹ of Z² is —N(R⁷)—, R⁷ is H, alkyl,substituted alkyl, heteroalkyl, carbocyclyl, substituted carbocyclyl,heterocyclyl, or substituted heterocyclyl, wherein alkyl, substitutedalkyl, heteroalkyl, carbocyclyl, substituted carbocyclyl, heterocyclyl,or substituted heterocyclyl are any alkyl, substituted alkyl,heteroalkyl, carbocyclyl, substituted carbocyclyl, heterocyclyl, orsubstituted heterocyclyl defined or exemplified herein.

In still another embodiment of the compounds of Formula I, Y isheterocyclyl or heterocyclylalkyl, wherein heterocyclyl andheterocyclylalkyl are any heterocyclyl or heterocyclylalkyl defined orexemplified herein. In a particular embodiment, Y is heterocyclylalkyl,e.g. thiazolylmethyl (—CH₂-thiazolyl).

In still another embodiment of the compounds of Formula I, X isheterocyclyl or heterocyclylalkyl, wherein heterocyclyl andheterocyclylalkyl are any heterocyclyl or heterocyclylalkyl defined orexemplified herein. In a particular embodiment, X is heterocyclylalkyl,e.g. thiazolylmethyl.

In still another embodiment of the compounds of Formula I, X and Y aredifferent, e.g., X and Y are different heterocyclyls, X and Y aredifferent heterocyclylalkyls, X is heterocyclyl and Y isheterocyclylalkyl, or X is heterocyclylalkyl and Y is heterocyclyl,wherein heterocyclyl and heterocyclylalkyl are any heterocyclyl orheterocyclylalkyl defined or exemplified herein.

In still another embodiment of the compounds of Formula I, X and Y arethe same. In a particular embodiment both X and Y areheterocyclylalkyls, e.g. thiazolylmethyl.

In still another embodiment of the compounds of Formula I, each Ar isaryl, substituted aryl, heteroaryl, or substituted heteroaryl, whereinthe aryl or heteroaryl are any aryl or heteroaryl defined or exemplifiedherein, and, when present, the substituents on the aryl or heteroarylinclude one or more of any substituents defined or exemplified herein.

In still another embodiment of the compounds of Formula I, each Ar isthe same, e.g., each Ar is an aryl such as phenyl.

In still another embodiment of the compounds of Formula I, each Ar isdifferent, e.g. one Ar is a substituted or unsubstituted aryl and theother Ar is a substituted or unsubstituted heteroaryl, each Ar is adifferent substituted or unsubstituted aryl, or each Ar is a differentsubstituted or unsubstituted heteroaryl, wherein aryl and heteroaryl areany aryl or heteroaryl defined or exemplified herein, and, when present,the substituents on the aryl or heteroaryl include one or more of anysubstituents defined or exemplified herein.

In still another embodiment of the compounds of Formula I, R¹, R³, andR⁵ are each independently H, alkyl, or substituted alkyl, wherein alkyland substituted alkyl include any of the alkyl or substituted alkylsdefined or disclosed herein.

In still another embodiment of the compounds of Formula I, R¹, R³, andR⁵ are each the same. In a particular embodiment R¹, R³, and R⁵ are eachH. In another particular embodiment R¹, R³, and R⁵ are each alkyl, e.g.one of the alkyl groups defined or disclosed herein.

In still another embodiment of the compounds of Formula I, R¹, R³, andR⁵ are each different.

In still another embodiment of the compounds of Formula I, one of R¹,R³, and R⁵ is different from the other two groups.

In still another embodiment of the compounds of Formula I, n and m areboth 1, and each R² is independently H, alkyl, substituted alkyl,arylheteroalkyl, arylalkyl, or heterocyclylalkyl, wherein alkyl,substituted alkyl arylheteroalkyl, aryl alkyl, or heterocyclylalkyl isany alkyl, substituted alkyl arylheteroalkyl, aryl alkyl, orheterocyclylalkyl defined or disclosed herein.

In still another embodiment of the compounds of Formula I, n and m areboth 1, and R² is H.

In still another embodiment of the compounds of Formula I, n is l, m is2, and R² is H.

In still another embodiment of the compounds of Formula I, n and m areboth 1, and at least one R² is alkyl. In a particular embodiment atleast one R² is methyl. In another particular embodiment at least one R²is ethyl. In another particular embodiment at least one R² is i-propyl.In another particular embodiment at least one R² is t-butyl. In anotherparticular embodiment, one R² is H, and the other R² is methyl. Inanother particular embodiment, one R² is H, and the other R² is ethyl.In another particular embodiment, one R² is H, and the other R² isi-propyl. In another particular embodiment, one R² is H, and the otherR² is t-butyl.

In still another embodiment of the compounds of Formula I, n and m areboth 1, and R² is substituted alkyl. In a particular embodiment at leastone R² is —CH(CH₃)OH or —CH(CH₃)O(t-Bu)

In still another embodiment of the compounds of Formula I, n and m areboth 1, and at least one R² is arylheteroalkyl. In particular embodimentn and m are both 1, and at least one R² is selected from the groupconsisting of H, methyl, ethyl, benzyl-O—CH₂—, i-propyl, —CH(CH₃)OBn,—CH₂CH(CH₃)—O-tBu, —CH(CH₃)OH, —CH₂OH, —CH₂OtBu, —CH₂CH₂NH₂, —CH₂CH₂NH—P(where P is a protecting group such as Boc, Ac, methanesulfonyl, etc.),—CH₂CH₂-morpholine, —CH₂C(O)OH, —CH₂C(O)OtBu, and —CH₂C(O)—NH₂.

In still another embodiment of the compounds of Formula I, n and m areboth 1, and at least one R² is arylheteroalkyl. In particular embodimentn and m are both 1, one R² is H and one R² is selected from the groupconsisting of H, methyl, ethyl, benzyl-O—CH₂—, i-propyl, —CH(CH₃)OBn,—CH₂CH(CH₃)—O-tBu, —CH(CH₃)OH, —CH₂OH, —CH₂OtBu, —CH₂CH₂NH₂, —CH₂CH₂NH—P(where P is a protecting group such as Boc, Ac, methanesulfonyl, etc.),—CH₂CH₂-morpholine, —CH₂C(O)OH, —CH₂C(O)OtBu, and —CH₂C(O)—NH₂.

In still another embodiment of the compounds of Formula I, R⁴ is H,alkyl, substituted alkyl, and heteroalkyl, wherein alkyl, substitutedalkyl, and heteroalkyl are any alkyl, substituted alkyl, or heteroalkyldefined or disclosed herein. A particular embodiment, R⁴ is H.

In still another embodiment of the compounds of Formula I, R⁶ is H,alkyl, substituted alkyl, and heteroalkyl, wherein alkyl, substitutedalkyl, and heteroalkyl are any alkyl, substituted alkyl, or heteroalkyldefined or disclosed herein. A particular embodiment, R⁶ is H.

In still another embodiment of the compounds of Formula I, R⁸ and R⁹ areeach one or more substituents independently selected from the groupconsisting of H, alkyl, substituted alkyl, halogen, aryl, substitutedaryl, heterocyclyl, substituted heterocyclyl, and —CN, wherein when R⁸or R⁹ are alkyl, substituted alkyl, halogen, aryl, substituted aryl,heterocyclyl, or substituted heterocyclyl, said alkyl, substitutedalkyl, halogen, aryl, substituted aryl, heterocyclyl, or substitutedheterocyclyl are any such groups defined or disclosed herein.

In still another embodiment of the compounds of Formula I, R⁸ and R⁹ arethe same. In a particular embodiment R⁸ and R⁹ are both H.

In still another embodiment of the compounds of Formula I, R⁸ and R⁹ aredifferent. In a particular embodiment R⁸ is alkyl and R⁹ is H. Inanother particular embodiment, R⁸ is i-propyl and R⁹ is H.

In yet another embodiment of the compounds of Formula I, at least one ofthe -L³-A-(L⁴-Ar)_(p) moieties is an -alkylene-aryl group, wherein saidalkylene and aryl moieties are any alkylene and aryl moieties defined orexemplified herein, optionally substituted on the alkylene and/or arylwith one or more of any substituents defined or exemplified herein.

In yet another embodiment of the compounds of Formula I, at least one ofthe -L³-A-(L⁴-Ar)_(p) moieties is an -alkylene-aryl-alkylene-aryl group,wherein said alkylene and aryl moieties are any alkylene and arylmoieties defined or exemplified herein, optionally substituted on thealkylene and/or aryl with one or more of any substituents defined orexemplified herein.

In yet another embodiment of the compounds of Formula I, at least one ofthe -L³-A-(L⁴-Ar)_(p) moieties is an -alkylene-aryl-alkylene-heteroarylgroup, wherein said alkylene, aryl, and heteroaryl moieties are anyalkylene, aryl, and heteroaryl moieties defined or exemplified herein,optionally substituted on the alkylene and/or aryl, and/or heteroarylwith one or more of any substituents defined or exemplified herein.

In yet another embodiment of the compounds of Formula I, at least one ofthe -L³-A-(L⁴-Ar)_(p) moieties is an-alkylene-heteroaryl-alkylene-heteroaryl group, wherein said alkyleneand heteroaryl moieties are any alkylene and heteroaryl moieties definedor exemplified herein, optionally substituted on the alkylene and/orheteroaryl with one or more of any substituents defined or exemplifiedherein.

In yet another embodiment of the compounds of Formula I, at least one ofthe -L³-A-(L⁴-Ar)_(p) moieties is an -alkylene-heteroaryl-alkylene-arylgroup, wherein said alkylene, aryl, and heteroaryl moieties are anyalkylene, aryl, and heteroaryl moieties defined or exemplified herein,optionally substituted on the alkylene and/or aryl, and/or heteroarylwith one or more of any substituents defined or exemplified herein.

In yet another embodiment of the compounds of Formula I, at least one ofthe -L³-A-(L⁴-Ar)_(p) moieties is an -alkylene-aryl-aryl group, whereinsaid alkylene and aryl moieties are any alkylene and aryl moietiesdefined or exemplified herein, optionally substituted on the alkyleneand/or aryl with one or more of any substituents defined or exemplifiedherein.

In yet another embodiment of the compounds of Formula I, at least one ofthe -L³-A-(L⁴-Ar)_(p) moieties is an -alkylene-aryl-O-aryl group,wherein said alkylene and aryl moieties are any alkylene and arylmoieties defined or exemplified herein, optionally substituted on thealkylene and/or aryl with one or more of any substituents defined orexemplified herein.

In yet another embodiment of the compounds of Formula I, at least one ofthe -L³-A-(L⁴-Ar)_(p) moieties is an -alkylene-aryl-CH₂—O-aryl group,wherein said alkylene and aryl moieties are any alkylene and arylmoieties defined or exemplified herein, optionally substituted on thealkylene and/or aryl with one or more of any substituents defined orexemplified herein.

In yet another embodiment of the compounds of Formula I, at least one ofthe -L³-A-(L⁴-Ar)_(p) moieties is an -alkylene-aryl-OCH₂-aryl group,wherein said alkylene and aryl moieties are any alkylene and arylmoieties defined or exemplified herein, optionally substituted on thealkylene and/or aryl with one or more of any substituents defined orexemplified herein.

In yet another embodiment of the compounds of Formula I, at least one ofthe -L³-A-(L⁴-Ar)_(p) moieties is an -alkylene-aryl-NH-aryl group,wherein said alkylene and aryl moieties are any alkylene and arylmoieties defined or exemplified herein, optionally substituted on thealkylene and/or aryl with one or more of any substituents defined orexemplified herein.

In yet another embodiment of the compounds of Formula I, at least one ofthe -L³-A-(L⁴-Ar)_(p) moieties is an -alkylene-aryl-heterocyclyl group,wherein said alkylene, aryl, and heterocyclyl moieties are any alkylene,aryl, and heterocyclyl moieties defined or exemplified herein,optionally substituted on the alkylene and/or aryl and/or heterocyclylwith one or more of any substituents defined or exemplified herein.

In yet another embodiment of the compounds of Formula I, at least one ofthe -L³-A-(L⁴-Ar)_(p) moieties is an -alkylene-aryl-O-heterocyclylgroup, wherein said alkylene, aryl, and heterocyclyl moieties are anyalkylene, aryl, and heterocyclyl moieties defined or exemplified herein,optionally substituted on the alkylene and/or aryl and/or heterocyclylwith one or more of any substituents defined or exemplified herein.

In yet another embodiment of the compounds of Formula I, at least one ofthe -L³-A-(L⁴-Ar)_(p) moieties is an -alkylene-aryl-CH₂—O-heterocyclylgroup, wherein said alkylene, aryl, and heterocyclyl moieties are anyalkylene, aryl, and heterocyclyl moieties defined or exemplified herein,optionally substituted on the alkylene and/or aryl and/or heterocyclylwith one or more of any substituents defined or exemplified herein.

In yet another embodiment of the compounds of Formula I, at least one ofthe -L³-A-(L⁴-Ar)_(p) moieties is an -alkylene-aryl-OCH₂-heterocyclylgroup, wherein said alkylene, aryl, and heterocyclyl moieties are anyalkylene, aryl, and heterocyclyl moieties defined or exemplified herein,optionally substituted on the alkylene and/or aryl and/or heterocyclylwith one or more of any substituents defined or exemplified herein.

In yet another embodiment of the compounds of Formula I, at least one ofthe -L³-A-(L⁴-Ar)_(p) moieties is an -alkylene-aryl-NH-heterocyclylgroup, wherein said alkylene, aryl, and heterocyclyl moieties are anyalkylene, aryl, and heterocyclyl moieties defined or exemplified herein,optionally substituted on the alkylene and/or aryl and/or heterocyclylwith one or more of any substituents defined or exemplified herein.

In yet another embodiment of the compounds of Formula I, at least one ofthe -L³-A-(L⁴-Ar)_(p) moieties is an -alkylene-heterocyclyl-aryl group,wherein said alkylene, aryl, and heterocyclyl moieties are any alkylene,aryl, and heterocyclyl moieties defined or exemplified herein,optionally substituted on the alkylene and/or aryl and/or heterocyclylwith one or more of any substituents defined or exemplified herein.

In yet another embodiment of the compounds of Formula I, at least one ofthe -L³-A-(L⁴-Ar)_(p) moieties is an -alkylene-heterocyclyl-O-arylgroup, wherein said alkylene, aryl, and heterocyclyl moieties are anyalkylene, aryl, and heterocyclyl moieties defined or exemplified herein,optionally substituted on the alkylene and/or aryl and/or heterocyclylwith one or more of any substituents defined or exemplified herein.

In yet another embodiment of the compounds of Formula I, at least one ofthe -L³-A-(L⁴-Ar)_(p) moieties is an -alkylene-heterocyclyl-CH₂—O-arylgroup, wherein said alkylene, aryl, and heterocyclyl moieties are anyalkylene, aryl, and heterocyclyl moieties defined or exemplified herein,optionally substituted on the alkylene and/or aryl and/or heterocyclylwith one or more of any substituents defined or exemplified herein.

In yet another embodiment of the compounds of Formula I, at least one ofthe -L³-A-(L⁴-Ar)_(p) moieties is an -alkylene-heterocyclyl-OCH₂-arylgroup, wherein said alkylene, aryl, and heterocyclyl moieties are anyalkylene, aryl, and heterocyclyl moieties defined or exemplified herein,optionally substituted on the alkylene and/or aryl and/or heterocyclylwith one or more of any substituents defined or exemplified herein.

In yet another embodiment of the compounds of Formula I, at least one ofthe -L³-A-(L⁴-Ar)_(p) moieties is an -alkylene-heterocyclyl-NH-arylgroup, wherein said alkylene, aryl, and heterocyclyl moieties are anyalkylene, aryl, and heterocyclyl moieties defined or exemplified herein,optionally substituted on the alkylene and/or aryl and/or heterocyclylwith one or more of any substituents defined or exemplified herein.

In yet another embodiment of the compounds of Formula I, at least one ofthe -L³-A-(L⁴-Ar)_(p) moieties is an -alkylene-heterocyclyl-heterocyclylgroup, wherein said alkylene, aryl, and heterocyclyl moieties are anyalkylene, aryl, and heterocyclyl moieties defined or exemplified herein,optionally substituted on the alkylene and/or aryl and/or heterocyclylwith one or more of any substituents defined or exemplified herein.

In yet another embodiment of the compounds of Formula I, at least one ofthe -L³-A-(L⁴-Ar)_(p) moieties is an-alkylene-heterocyclyl-O-heterocyclyl group, wherein said alkylene,aryl, and heterocyclyl moieties are any alkylene, aryl, and heterocyclylmoieties defined or exemplified herein, optionally substituted on thealkylene and/or aryl and/or heterocyclyl with one or more of anysubstituents defined or exemplified herein.

In yet another embodiment of the compounds of Formula I, at least one ofthe -L³-A-(L⁴-Ar)_(p) moieties is an-alkylene-heterocyclyl-CH₂—O-heterocyclyl group, wherein said alkylene,aryl, and heterocyclyl moieties are any alkylene, aryl, and heterocyclylmoieties defined or exemplified herein, optionally substituted on thealkylene and/or aryl and/or heterocyclyl with one or more of anysubstituents defined or exemplified herein.

In yet another embodiment of the compounds of Formula I, at least one ofthe -L³-A-(L⁴-Ar)_(p) moieties is an-alkylene-heterocyclyl-OCH₂-heterocyclyl group, wherein said alkylene,aryl, and heterocyclyl moieties are any alkylene, aryl, and heterocyclylmoieties defined or exemplified herein, optionally substituted on thealkylene and/or aryl and/or heterocyclyl with one or more of anysubstituents defined or exemplified herein.

In yet another embodiment of the compounds of Formula I, at least one ofthe -L³-A-(L⁴-Ar)_(p) moieties is an-alkylene-heterocyclyl-NH-heterocyclyl group, wherein said alkylene,aryl, and heterocyclyl moieties are any alkylene, aryl, and heterocyclylmoieties defined or exemplified herein, optionally substituted on thealkylene and/or aryl and/or heterocyclyl with one or more of anysubstituents defined or exemplified herein.

In yet another embodiment of the compounds of Formula I, at least one ofthe -L³-A-(L⁴-Ar)_(p) moieties is an -alkylene-aryl-heteroaryl group,wherein said alkylene, aryl, and heteroaryl moieties are any alkylene,aryl, and heteroaryl moieties defined or exemplified herein, optionallysubstituted on the alkylene and/or aryl and/or heteroaryl with one ormore of any substituents defined or exemplified herein.

In yet another embodiment of the compounds of Formula I, at least one ofthe -L³-A-(L⁴-Ar)_(p) moieties is an -alkylene-aryl-O-heteroaryl group,wherein said alkylene, aryl, and heteroaryl moieties are any alkylene,aryl, and heteroaryl moieties defined or exemplified herein, optionallysubstituted on the alkylene and/or aryl and/or heteroaryl with one ormore of any substituents defined or exemplified herein.

In yet another embodiment of the compounds of Formula I, at least one ofthe -L³-A-(L⁴-Ar)_(p) moieties is an -alkylene-aryl-CH₂—O-heteroarylgroup, wherein said alkylene, aryl, and heteroaryl moieties are anyalkylene, aryl, and heteroaryl moieties defined or exemplified herein,optionally substituted on the alkylene and/or aryl and/or heteroarylwith one or more of any substituents defined or exemplified herein.

In yet another embodiment of the compounds of Formula I, at least one ofthe -L³-A-(L⁴-Ar)_(p) moieties is an -alkylene-aryl-OCH₂-heteroarylgroup, wherein said alkylene, aryl, and heteroaryl moieties are anyalkylene, aryl, and heteroaryl moieties defined or exemplified herein,optionally substituted on the alkylene and/or aryl and/or heteroarylwith one or more of any substituents defined or exemplified herein.

In yet another embodiment of the compounds of Formula I, at least one ofthe -L³-A-(L⁴-Ar)_(p) moieties is an -alkylene-aryl-NH-heteroaryl group,wherein said alkylene, aryl, and heteroaryl moieties are any alkylene,aryl, and heteroaryl moieties defined or exemplified herein, optionallysubstituted on the alkylene and/or aryl and/or heteroaryl with one ormore of any substituents defined or exemplified herein.

In yet another embodiment of the compounds of Formula I, at least one ofthe -L³-A-(L⁴-Ar)_(p) moieties is an -alkylene-heteroaryl-aryl group,wherein said alkylene, aryl, and heteroaryl moieties are any alkylene,aryl, and heteroaryl moieties defined or exemplified herein, optionallysubstituted on the alkylene and/or aryl and/or heteroaryl with one ormore of any substituents defined or exemplified herein.

In yet another embodiment of the compounds of Formula I, at least one ofthe -L³-A-(L⁴-Ar)_(p) moieties is an -alkylene-heteroaryl-O-aryl group,wherein said alkylene, aryl, and heteroaryl moieties are any alkylene,aryl, and heteroaryl moieties defined or exemplified herein, optionallysubstituted on the alkylene and/or aryl and/or heteroaryl with one ormore of any substituents defined or exemplified herein.

In yet another embodiment of the compounds of Formula I, at least one ofthe -L³-A-(L⁴-Ar)_(p) moieties is an -alkylene-heteroaryl-CH₂—O-arylgroup, wherein said alkylene, aryl, and heteroaryl moieties are anyalkylene, aryl, and heteroaryl moieties defined or exemplified herein,optionally substituted on the alkylene and/or aryl and/or heteroarylwith one or more of any substituents defined or exemplified herein.

In yet another embodiment of the compounds of Formula I, at least one ofthe -L³-A-(L⁴-Ar)_(p) moieties is an -alkylene-heteroaryl-OCH₂-arylgroup, wherein said alkylene, aryl, and heteroaryl moieties are anyalkylene, aryl, and heteroaryl moieties defined or exemplified herein,optionally substituted on the alkylene and/or aryl and/or heteroarylwith one or more of any substituents defined or exemplified herein.

In yet another embodiment of the compounds of Formula I, at least one ofthe -L³-A-(L⁴-Ar)_(p) moieties is an -alkylene-heteroaryl-NH-aryl group,wherein said alkylene, aryl, and heteroaryl moieties are any alkylene,aryl, and heteroaryl moieties defined or exemplified herein, optionallysubstituted on the alkylene and/or aryl and/or heteroaryl with one ormore of any substituents defined or exemplified herein.

In yet another embodiment of the compounds of Formula I, at least one ofthe -L³-A-(L⁴-Ar)_(p) moieties is an -alkylene-heterocyclyl-heteroarylgroup, wherein said alkylene, aryl, and heteroaryl moieties are anyalkylene, aryl, and heteroaryl moieties defined or exemplified herein,optionally substituted on the alkylene and/or aryl and/or heteroarylwith one or more of any substituents defined or exemplified herein.

In yet another embodiment of the compounds of Formula I, at least one ofthe -L³-A-(L⁴-Ar)_(p) moieties is an -alkylene-heterocyclyl-O-heteroarylgroup, wherein said alkylene, aryl, and heteroaryl moieties are anyalkylene, aryl, and heteroaryl moieties defined or exemplified herein,optionally substituted on the alkylene and/or aryl and/or heteroarylwith one or more of any substituents defined or exemplified herein.

In yet another embodiment of the compounds of Formula I, at least one ofthe -L³-A-(L⁴-Ar)_(p) moieties is an-alkylene-heterocyclyl-CH₂—O-heteroaryl group, wherein said alkylene,aryl, and heteroaryl moieties are any alkylene, aryl, and heteroarylmoieties defined or exemplified herein, optionally substituted on thealkylene and/or aryl and/or heteroaryl with one or more of anysubstituents defined or exemplified herein.

In yet another embodiment of the compounds of Formula I, at least one ofthe -L³-A-(L⁴-Ar)_(p) moieties is an-alkylene-heteroaryl-OCH₂-heteroaryl group, wherein said alkylene, aryl,and heteroaryl moieties are any alkylene, aryl, and heteroaryl moietiesdefined or exemplified herein, optionally substituted on the alkyleneand/or aryl and/or heteroaryl with one or more of any substituentsdefined or exemplified herein.

In yet another embodiment of the compounds of Formula I, at least one ofthe -L³-A-(L⁴-Ar)_(p) moieties is an -alkylene-heteroaryl-NH-heteroarylgroup, wherein said alkylene, aryl, and heteroaryl moieties are anyalkylene, aryl, and heteroaryl moieties defined or exemplified herein,optionally substituted on the alkylene and/or aryl and/or heteroarylwith one or more of any substituents defined or exemplified herein.

In yet another embodiment of the compounds of Formula I, at least one ofthe -L³-A-(L⁴-Ar)_(p) moieties is an alkyl group.

In yet another embodiment of the compounds of Formula I, both of the-L³-A-(L⁴-Ar)_(p) moieties are alkyl groups, wherein the alkyl groupsare the same or different.

In yet another embodiment of the compounds of Formula I, both-L³-A-(L⁴-Ar)_(p) moieties are —CH₂-phenyl and X and Y are both—CH₂-heterocyclyl.

In yet another embodiment of the compounds of Formula I, both-L³-A-(L⁴-Ar)_(p) moieties are —CH₂-phenyl and Y is —CH₂-heterocyclyl.

In yet another embodiment of the compounds of Formula I, both-L³-A-(L⁴-Ar)_(p) moieties are —CH₂-phenyl and X is —CH₂-heterocyclyl.

In yet another embodiment of the compounds of Formula I, both-L³-A-(L⁴-Ar)_(p) moieties are —CH₂-phenyl and Y is —CH₂-thiazolyl.

In yet another embodiment of the compounds of Formula I, both-L³-A-(L⁴-Ar)_(p) moieties are —CH₂-phenyl and X is —CH₂-thiazolyl.

In yet another embodiment of the compounds of Formula I, both-L³-A-(L⁴-Ar)_(p) moieties are —CH₂-phenyl and X and Y are both—CH₂-thiazolyl.

In yet another embodiment of the compounds of Formula I, both-L³-A-(L⁴-Ar)_(p) moieties are —CH₂-phenyl, X and Y are both—CH₂-thiazolyl, and n and m are both 1.

In yet another embodiment of the compounds of Formula I, both-L³-A-(L⁴-Ar)_(p) moieties are —CH₂-phenyl, X and Y are both—CH₂-thiazolyl, n and m are both 1, and at least one R² is a C₁-C₆alkyl.

In yet another embodiment of the compounds of Formula I, both-L³-A-(L⁴-Ar)_(p) moieties are —CH₂-phenyl, X and Y are both—CH₂-thiazolyl, n and m are both 1, and at least one R² is a C₁-C₆hydroxyalkyl.

In yet another embodiment of the compounds of Formula I, both-L³-A-(L⁴-Ar)_(p) moieties are —CH₂-phenyl, X and Y are both—CH₂-thiazolyl, n and m are both 1, and at least one R² is a C₂-C₁₀alkoxyalkyl.

In yet another embodiment of the compounds of Formula I, both-L³-A-(L⁴-Ar)_(p) moieties are —CH₂-phenyl, X and Y are both—CH₂-thiazolyl, n and m are both 1, and at least one R² is a C₇-C₁₄arylalkyloxyalkyl.

In yet another embodiment of the compounds of Formula I, both-L³-A-(L⁴-Ar)_(p) moieties are —CH₂-phenyl, X and Y are both—CH₂-thiazolyl, n and m are both 1, and at least one R² is a C₁-C₆aminoalkyl.

In yet another embodiment of the compounds of Formula I, both-L³-A-(L⁴-Ar)_(p) moieties are —CH₂-phenyl, X and Y are both—CH₂-thiazolyl, n and m are both 1, and at least one R² is a C₁-C₆aminoalkyl substituted on the nitrogen with an amine protecting groupselected from acyl, alkylsulfonyl, arylsulfonyl, heterocyclylacyl, andbenzyl.

In yet another embodiment of the compounds of Formula I, both-L³-A-(L⁴-Ar)_(p) moieties are —CH₂-phenyl, X and Y are both—CH₂-thiazolyl, n and m are both 1, and at least one R² is a substitutedor unsubstituted heterocyclylalkyl.

In yet another embodiment of the compounds of Formula I, both-L³-A-(L⁴-Ar)_(p) moieties are —CH₂-phenyl, X and Y are both—CH₂-thiazolyl, n and m are both 1, and L² is —CH₂—.

In yet another embodiment of the compounds of Formula I, at least one-L³-A-(L⁴-Ar)_(p) moiety is —CH₂-phenyl-CH₂-phenyl.

In yet another embodiment of the compounds of Formula I, at least one-L³-A-(L⁴-Ar)_(p) moiety is —CH₂-heteroaryl-CH₂-phenyl.

In yet another embodiment of the compounds of Formula I, at least one-L³-A-(L⁴-Ar)_(p) moiety is —CH₂-phenyl-CH₂-heteroaryl.

In yet another embodiment of the compounds of Formula I, at least one-L³-A-(L⁴-Ar)_(p) moiety is —CH₂-heteroaryl-CH₂-heteroaryl.

In yet another embodiment of the compounds of Formula I, X and Y areboth heterocyclylalkyl.

In yet another embodiment of the compounds of Formula I, X and Y areboth heteroarylalkyl.

In another embodiment of the compounds of Formula I, L¹ is —C(O)—, R⁴ isH, and both -L³-A-(L⁴-Ar)_(p) groups are substituted or unsubstitutedbenzyl.

In another embodiment of the compounds of Formula I, L¹ is —C(O)—, R⁴ isH, both -L³-A-(L⁴-Ar)_(p) groups are substituted or unsubstitutedbenzyl, and L² is —CH₂—.

In another embodiment of the compounds of Formula I, L¹ is —C(O)—, R⁴ isH, both -L³-A-(L⁴-Ar)_(p) groups are substituted or unsubstitutedbenzyl, L² is —CH₂—, and m and n are both 1.

In another embodiment of the compounds of Formula I, L¹ is —C(O)—, R⁴ isH, both -L³-A-(L⁴-Ar)_(p) groups are substituted or unsubstitutedbenzyl, L² is —CH₂—, m and n are both 1, and R¹ is H.

In another embodiment of the compounds of Formula I, L¹ is —C(O)—, R⁴ isH, both -L³-A-(L⁴-Ar)_(p) groups are substituted or unsubstitutedbenzyl, L² is —CH₂—, m and n are both 1, R¹ is H, and Z¹ is —N(alkyl)-.

In another embodiment of the compounds of Formula I, L¹ is —C(O)—, R⁴ isH, both -L³-A-(L⁴-Ar)_(p) groups are substituted or unsubstitutedbenzyl, L² is —CH₂—, m and n are both 1, R¹ is H, and Z¹ is —N(CH₃)—.

In another embodiment of the compounds of Formula I, L¹ is —C(O)—, R⁴ isH, both -L³-A-(L⁴-Ar)_(p) groups are substituted or unsubstitutedbenzyl, L² is —CH₂—, m and n are both 1, R¹ is H, Z¹ is —N(alkyl)-, andZ² is —O—.

In another embodiment of the compounds of Formula I, L¹ is —C(O)—, R⁴ isH, both -L³-A-(L⁴-Ar)_(p) groups are substituted or unsubstitutedbenzyl, L² is —CH₂—, m and n are both 1, R¹ is H, Z¹ is —N(CH₃)—, and Z²is —O—.

In another embodiment of the compounds of Formula I, L¹ is —C(O)—, R⁴ isH, both -L³-A-(L⁴-Ar)_(p) groups are substituted or unsubstitutedbenzyl, L² is —CH₂—, m and n are both 1, R¹ is H, Z¹ is —N(alkyl)-, Z²is —O—, and Y is substituted or unsubstituted —CH₂-4-thiazole.

In another embodiment of the compounds of Formula I, L¹ is —C(O)—, R⁴ isH, both -L³-A-(L⁴-Ar)_(p) groups are substituted or unsubstitutedbenzyl, L² is —CH₂—, m and n are both 1, R¹ is H, Z¹ is —N(alkyl)-, Z²is —O—, and R⁸—Y is —CH₂-(2-alkyl-4-thiazole).

In another embodiment of the compounds of Formula I, L¹ is —C(O)—, R⁴ isH, both -L³-A-(L⁴-Ar)_(p) groups are substituted or unsubstitutedbenzyl, L² is —CH₂—, m and n are both 1, R¹ is H, Z¹ is —N(H)—, Z² is—O—, and R⁸—Y is —CH₂-(2-iPr-4-thiazole).

In another embodiment of the compounds of Formula I, L¹ is —C(O)—, R⁴ isH, both -L³-A-(L⁴-Ar)_(p) groups are substituted or unsubstitutedbenzyl, L² is —CH₂—, m and n are both 1, R¹ is H, Z¹ is —N(alkyl)-, Z²is —O—, Y is substituted or unsubstituted —CH₂-4-thiazole, and X issubstituted or unsubstituted —CH₂-5-thiazole.

In another embodiment of the compounds of Formula I, L¹ is —C(O)—, R⁴ isH, both -L³-A-(L⁴-Ar)_(p) groups are substituted or unsubstitutedbenzyl, L² is —CH₂—, m and n are both 1, R¹ is H, Z¹ is —N(alkyl)-, Z²is —O—, Y is substituted or unsubstituted —CH₂-4-thiazole, and X isunsubstituted —CH₂-5-thiazole.

In another embodiment of the compounds of Formula I, L¹ is —C(O)—, R⁴ isH, both -L³-A-(L⁴-Ar)_(p) groups are substituted or unsubstitutedbenzyl, L² is —CH₂—, m and n are both 1, R¹ is H, Z¹ is —N(H)—, Z² is—O—, R⁸—Y is —CH₂-(2-iPr-4-thiazole), and X is unsubstituted—CH₂-5-thiazole.

In another embodiment of the compounds of Formula I, each R² isindependently H or hydroxyalkyl.

In another embodiment of the compounds of Formula I, each R² isindependently H or heterocyclylalkyl.

In another embodiment of the compounds of Formula I, each R² isindependently H or —CH₂-heterocyclyl, wherein said heterocyclyl is a 5-or 6-membered ring having at least one ring nitrogen atom.

In another embodiment of the compounds of Formula I, each R² isindependently H or —CH₂-heterocyclyl, wherein said heterocyclyl is a6-membered ring having at least one ring nitrogen atom.

In another embodiment of the compounds of Formula I, each R² isindependently H or —CH₂-heterocyclyl, wherein said heterocyclyl is a6-membered ring having at least one ring nitrogen atom, where the —CH₂—moiety thereof is bonded to the ring nitrogen atom.

In another embodiment of the compounds of Formula I, each R² isindependently H or —CH₂-heterocyclyl, wherein said heterocyclyl isselected from the group consisting of piperadyl, piperazyl, andmorpholinyl.

In another embodiment of the compounds of Formula I, each R² isindependently H or —CH₂-heterocyclyl, wherein said heterocyclyl isselected from the group consisting of piperadyl, piperazyl, andmorpholinyl, and the —CH₂-moiety thereof is bonded to a ring nitrogenatom of the heterocyclyl.

In another embodiment of the compounds of Formula I, each R² isindependently H or aminoalkyl.

In another embodiment of the compounds of Formula I, each R² isindependently H or aminoalkyl substituted with an amine protecting groupselected from the group consisting of acetyl, alkylsulfonyl, Boc, Cbz,and Fmoc.

In another embodiment of the compounds of Formula I, each R² isindependently H or ethylacetamide (—CH₂CH₂NHC(O)CH₃).

In another embodiment of the compounds of Formula I, L¹ is —C(O)—, R⁴ isH, both -L³-A-(L⁴-Ar)_(p) groups are substituted or unsubstitutedbenzyl, L² is —CH₂—, m and n are both 1, R¹ is H, Z¹ is —N(H)—, Z² is—O—, R⁸—Y is —CH₂-(2-iPr-4-thiazole), X is unsubstituted—CH₂-5-thiazole, and R² is independently H or hydroxyalkyl.

In another embodiment of the compounds of Formula I, L¹ is —C(O)—, R⁴ isH, both -L³-A-(L⁴-Ar)_(p) groups are substituted or unsubstitutedbenzyl, L² is —CH₂—, m and n are both 1, R¹ is H, Z¹ is —N(H)—, Z² is—O—, R⁸—Y is —CH₂-(2-iPr-4-thiazole), X is unsubstituted—CH₂-5-thiazole, and one R² is H and the other R² is hydroxyalkyl.

In another embodiment of the compounds of Formula I, L¹ is —C(O)—, R⁴ isH, both -L³-A-(L⁴-Ar)_(p) groups are substituted or unsubstitutedbenzyl, L² is —CH₂—, m and n are both 1, R¹ is H, Z¹ is —N(H)—, Z² is—O—, R⁸—Y is —CH₂-(2-iPr-4-thiazole), X is unsubstituted—CH₂-5-thiazole, and one R² is H and the other R² is hydroxymethyl.

In another embodiment of the compounds of Formula I, L¹ is —C(O)—, R⁴ isH, both -L³-A-(L⁴-Ar)_(p) groups are substituted or unsubstitutedbenzyl, L² is —CH₂—, m and n are both 1, R¹ is H, Z¹ is —N(H)—, Z² is—O—, R⁸—Y is —CH₂-(2-iPr-4-thiazole), X is unsubstituted—CH₂-5-thiazole, and each R² is independently H or —CH₂-heterocyclyl,wherein said heterocyclyl is a 5- or 6-membered ring having at least onering nitrogen atom.

In another embodiment of the compounds of Formula I, L¹ is —C(O)—, R⁴ isH, both -L³-A-(L⁴-Ar)_(p) groups are substituted or unsubstitutedbenzyl, L² is —CH₂—, m and n are both 1, R¹ is H, Z¹ is —N(H)—, Z² is—O—, R⁸—Y is —CH₂-(2-iPr-4-thiazole), X is unsubstituted—CH₂-5-thiazole, and each R² is independently H or —CH₂-heterocyclyl,wherein said heterocyclyl is selected from the group consisting ofpiperadyl, piperazyl, and morpholinyl, and the —CH₂— moiety thereof isbonded to a ring nitrogen atom of the heterocyclyl.

In another embodiment of the compounds of Formula I, L¹ is —C(O)—, R⁴ isH, both -L³-A-(L⁴-Ar)_(p) groups are substituted or unsubstitutedbenzyl, L² is —CH₂—, m and n are both 1, R¹ is H, Z¹ is —N(H)—, Z² is—O—, R⁸—Y is —CH₂-(2-iPr-4-thiazole), X is unsubstituted—CH₂-5-thiazole, and one R² is H and the other R² is —CH₂-heterocyclyl,wherein said heterocyclyl is selected from the group consisting ofpiperadyl, piperazyl, and morpholinyl, and the —CH₂— moiety thereof isbonded to a ring nitrogen atom of the heterocyclyl.

In another embodiment of the compounds of Formula I, L¹ is —C(O)—, R⁴ isH, both -L³-A-(L⁴-Ar)_(p) groups are substituted or unsubstitutedbenzyl, L² is —CH₂—, m and n are both 1, R¹ is H, Z¹ is —N(H)—, Z² is—O—, R⁸—Y is —CH₂-(2-iPr-4-thiazole), X is unsubstituted—CH₂-5-thiazole, and each R² is independently H or aminoalkylsubstituted with an amine protecting group selected from the groupconsisting of acetyl, alkylsulfonyl, Boc, Cbz, and Fmoc.

In another embodiment of the compounds of Formula I, L¹ is —C(O)—, R⁴ isH, both -L³-A-(L⁴-Ar)_(p) groups are substituted or unsubstitutedbenzyl, L² is —CH₂—, m and n are both 1, R¹ is H, Z¹ is —N(H)—, Z² is—O—, R⁸—Y is —CH₂-(2-iPr-4-thiazole), X is unsubstituted—CH₂-5-thiazole, and one R² is H and the other R² is aminoalkylsubstituted with an amine protecting group selected from the groupconsisting of acetyl, alkylsulfonyl, Boc, Cbz, and Fmoc.

In another embodiment of the compounds of Formula I, L¹ is —C(O)—, R⁴ isH, both -L³-A-(L⁴-Ar)_(p) groups are substituted or unsubstitutedbenzyl, L² is —CH₂—, m and n are both 1, R¹ is H, Z¹ is —N(H)—, Z² is—O—, R⁸—Y is —CH₂-(2-iPr-4-thiazole), X is unsubstituted—CH₂-5-thiazole, and one R² is H and the other R² is ethylacetamide(—CH₂CH₂NHC(O)CH₃).

In another embodiment of the compounds of Formula I, L¹ is —C(O)—, R⁴ isH, both -L³-A-(L⁴-Ar)_(p) groups are substituted or unsubstitutedbenzyl, L² is —CH₂—, m and n are both 1, R¹ is H, Z¹ is —N(alkyl)-, Z²is —O—, and Y is substituted or unsubstituted —CH₂-thiazole.

In still another embodiment, the compounds of Formula I, orpharmaceutically acceptable salts, solvates, esters, or stereoisomersthereof, have the structure shown in Formula IIA:

wherein R¹¹ and R¹⁶ are each independently heterocyclyl or substitutedheterocyclyl; and R¹², R¹³, R¹⁴, and R¹⁵ are each independently H, —C₁₋₄alkyl or —C₁₋₄ substituted alkyl.

In still another embodiment of the compounds of Formula IIA, R¹³ is H,—C₁₋₄ alkyl, —(CH₂)₀₋₁CR¹⁷R¹⁸OR¹⁹, —(CH₂)₀₋₃CR¹⁷R¹⁸NR²⁰R²¹,—(CH₂)₀₋₃CR¹⁷R¹⁸NR¹⁷C(O)—NR²⁰R²¹, —(CH₂)₁₋₃C(O)R²², —(CH₂)₁₋₃S(O)₂R²² or—(CH₂)₁₋₃—R²³; R¹⁴ and R¹⁵ are each independently H, —C₁₋₄ alkyl orarylalkyl; R¹⁷ and R¹⁸ are each independently H or —C₁₋₃ alkyl; R¹⁹ isH, —C₁₋₄ alkyl or arylalkyl; R²⁰ and R²¹ are each independently H, —C₁₋₃alkyl, —C(O)R¹⁷ or —S(O)₂R¹⁷; or R²⁰ and R²¹, taken together with thenitrogen atom to which they are attached, form an unsubstituted orsubstituted 5-6 membered heterocyclyl ring containing 1-2 heteroatomsselected from the group consisting of N and O; R²² is H, —C₁₋₃ alkyl,—OR¹⁹ or —NR²⁰R²¹; and R²³ is an unsubstituted or substituted 5-6membered heterocyclyl ring containing 1-2 heteroatoms selected from thegroup consisting of N and O.

In still another embodiment of the compounds of Formula IIA, R¹³ is—(CH₂)₀₋₃CR¹⁷R¹⁸NR²⁰R²¹, —(CH₂)₀₋₃CR¹⁷R¹⁸NR¹⁷C(O)—NR²⁰R²¹, or—(CH₂)₁₋₃R²³ wherein R²⁰ and R²¹ form a 5-6 membered heterocyclyl ringcontaining 1-2 heteroatoms selected from the group consisting of N and Oor R²³ is an unsubstituted or substituted 5-6 membered heterocyclyl ringcontaining 1-2 heteroatoms selected from the group consisting of N andO, and the 5-6 membered heterocyclyl ring is optionally substituted witha C₁₋₂ alkyl.

In still another embodiment of the compounds of Formula IIA, R¹³ is—(CH₂)₀₋₁CR¹⁷R¹⁸OR¹⁹. In a particular embodiment, R¹³ is a C₁₋₂hydroxyalkyl or a C₁₋₆ alkoxyalkyl group.

In still another embodiment of the compounds of Formula IIA, R¹³ is—(CH₂)₀₋₃CR¹⁷R¹⁸NR²⁰R²¹. In a particular embodiment, R¹³ is aC₁₋₄alkylene-NH₂ group, C₁₋₄alkylene-NHP (wherein P is a protectinggroup such as Boc, Fmoc, Cbz, Ac, trifluoroacetyl, toluenesulfony group,benzyl, etc.), or C₁₋₄alkylene-N(alkyl)₂ group.

In still another embodiment of the compounds of Formula IIA, R¹³ is—(CH₂)₀₋₃CR¹⁷R¹⁸NR¹⁷C(O)—NR²⁰R²¹. In a particular embodiment, R¹³ is aC₁₋₄alkylene-C(O)NH₂ group or C₁₋₄alkylene-C(O)N(alkyl)₂ group.

In still another embodiment of the compounds of Formula IIA, R¹¹, R¹²,R¹³, R¹⁴, R¹⁵, and R¹⁶ are each independently selected from the groupsshown in the Table, below:

R¹¹ R¹² R¹³ R¹⁴ R¹⁵ R¹⁶

H

Me

Et Et

Me Me

H H

In still another embodiment of the compounds of Formula IIA, R¹¹ issubstituted or unsubstituted heterocyclyl, R¹² is alkyl, R¹³ issubstituted or unsubstituted heterocyclylalkyl, R¹⁴ and R¹⁵ are eachindependently substituted or unsubstituted arylalkyl, and R¹⁶ issubstituted or unsubstituted heterocyclyl.

In still another embodiment of the compounds of Formula IIA, R¹¹ issubstituted heterocyclyl R¹² is alkyl, R¹³ is unsubstitutedheterocyclylalkyl, R¹⁴ and R¹⁵ are both unsubstituted arylalkyl, and R¹⁶is unsubstituted heterocyclyl.

In still another embodiment of the compounds of Formula IIA, R¹¹ issubstituted or unsubstituted heterocyclyl, R¹² is alkyl R¹³ ishydroxyalkyl, R¹⁴ and R¹⁵ are each independently substituted orunsubstituted arylalkyl, and R¹⁶ is substituted or unsubstitutedheterocyclyl.

In still another embodiment of the compounds of Formula IIA, R¹¹ issubstituted heterocyclyl, R¹² is alkyl R¹³ is hydroxyalkyl, R¹⁴ and R¹⁵are both unsubstituted arylalkyl, and R¹⁶ is unsubstituted heterocyclyl.

In still another embodiment of the compounds of Formula IIA, R¹¹ issubstituted or unsubstituted heterocyclyl, R¹² is alkyl, R¹³ isprotected or unprotected aminoalkyl, R¹⁴ and R¹⁵ are each independentlysubstituted or unsubstituted arylalkyl, and R¹⁶ is substituted orunsubstituted heterocyclyl.

In still another embodiment of the compounds of Formula IIA, R¹¹ issubstituted heterocyclyl, R¹² is alkyl, R¹³ is protected aminoalkyl, R¹⁴and R¹⁵ are both unsubstituted arylalkyl, and R¹⁶ is unsubstitutedheterocyclyl.

In still another embodiment of the compounds of Formula IIA, R¹¹ issubstituted heterocyclyl, R¹² is alkyl, R¹³ is acylated aminoalkyl, R¹⁴and R¹⁵ are both unsubstituted arylalkyl, and R¹⁶ is unsubstitutedheterocyclyl.

In another embodiment, the compounds of Formula I, or pharmaceuticallyacceptable salts, solvates, stereoisomers and/or esters thereof, havethe following structure IIB:

R^(10a) and R^(11b) are each independently H or —C₁₋₄ alkyl; R¹² is H or—CH₃; R¹³ is H, —C₁₋₄ alkyl, —(CH₂)₀₋₁CR¹⁷R¹⁸OR¹⁹,—(CH₂)₀₋₃CR¹⁷R¹⁸NR²⁰R²¹, —(CH₂)₀₋₃CR¹⁷R¹⁸NR¹⁷C(O)NR²⁰R²¹,—(CH₂)₁₋₃C(O)R²², —(CH₂)₁₋₃S(O)₂R²² or —(CH₂)₁₋₃—R²³; R¹⁴ and R¹⁵ areeach independently H, —C₁₋₄ alkyl or arylalkyl; R¹⁷ and R¹⁸ are eachindependently H or —C₁₋₃ alkyl; R¹⁹ is H, —C₁₋₄ alkyl or arylalkyl; R²⁰and R²¹ are each independently H, —C₁₋₃ alkyl, —C(O)R¹⁷ or —S(O)₂R¹⁷; orR²⁰ and R²¹, taken together with the nitrogen atom to which they areattached, form an unsubstituted or substituted 5-6 membered heterocyclylring containing 1-2 heteroatoms selected from the group consisting of Nand O; R²² is H, —C₁₋₃alkyl, —OR¹⁹ or —NR²⁰R²¹; and R²³ is anunsubstituted or substituted 5-6 membered heterocyclyl ring containing1-2 heteroatoms selected from the group consisting of N and O.

In still another embodiment of the compounds of Formula IIB, R¹³ is—(CH₂)₀₋₃CR¹⁷R¹⁸NR²⁰R²¹, —(CH₂)₀₋₃CR¹⁷R¹⁸NR¹⁷C(O)—NR²⁰R²¹, or—(CH₂)₁₋₃—R²³ wherein R²⁰ and R²¹ form a 5-6 membered heterocyclyl ringcontaining 1-2 heteroatoms selected from the group consisting of N and Oor R²³ is an unsubstituted or substituted 5-6 membered heterocyclyl ringcontaining 1-2 heteroatoms selected from the group consisting of N andO, and the 5-6 membered heterocyclyl ring is optionally substituted witha C₁₋₂ alkyl.

In another embodiment, the compounds of Formula I, or pharmaceuticallyacceptable salts, solvates, stereoisomers and/or esters thereof, havethe following structure IIC:

wherein: R¹³ is H, —C₁₋₄ alkyl, —(CH₂)₀₋₁CR¹⁷R¹⁸OR¹⁹,—(CH₂)₀₋₃CR¹⁷R¹⁸NR²⁰R²¹, —(CH₂)₀₋₃CR¹⁷R¹⁸NR¹⁷C(O)NR²⁰R²¹,—(CH₂)₁₋₃C(O)R²² or —(CH₂)₁₋₃—R²³; R¹⁷ and R¹⁸ are each independently Hor C₁₋₃ alkyl; R¹⁹ is H, —C₁₋₄ alkyl or arylalkyl; R²⁰ and R²¹ are eachindependently H, —C₁₋₃ alkyl, —C(O)R¹⁷ or —S(O)₂R¹⁷; or R²⁰ and R²¹,taken together with the nitrogen atom to which they are attached, form a5-6 membered heterocyclyl ring containing 1-2 heteroatoms selected fromthe group consisting of N and O; R²² is H, —C₁₋₃alkyl, —OR¹⁹ or—NR²⁰R²¹; and R²³ is a 5-6 membered heterocyclyl ring containing 1-2heteroatoms selected from the group consisting of N and O.

In still another embodiment of the compounds of Formula IIC, R¹³ is—(CH₂)₀₋₃CR¹⁷R¹⁸NR²⁰R²¹, —(CH₂)₀₋₃CR¹⁷R¹⁸NR¹⁷C(O)—NR²⁰R²¹, or—(CH₂)₁₋₃—R²³ wherein R²⁰ and R²¹ form a 5-6 membered heterocyclyl ringcontaining 1-2 heteroatoms selected from the group consisting of N and Oor R²³ is an unsubstituted or substituted 5-6 membered heterocyclyl ringcontaining 1-2 heteroatoms selected from the group consisting of N andO, and the 5-6 membered heterocyclyl ring is optionally substituted witha C₁₋₂ alkyl.

In still another embodiment of the compounds of Formula IIC, R¹³ is—(CH₂)₀₋₃CR¹⁷R¹⁸NR²⁰R²¹. In a particular embodiment, R¹³ is aC₁₋₄alkylene-NH₂ group, C₁₋₄alkylene-NHP (wherein P is a protectinggroup such as Boc, Fmoc, Cbz, Ac, trifluoroacetyl, toluenesulfony group,benzyl, etc.), or C₁₋₄alkylene-N(alkyl)₂ group.

In still another embodiment of the compounds of Formula IIC, R¹³ is—(CH₂)₀₋₃CR¹⁷R¹⁸NR¹⁷C(O)—NR²⁰R²¹. In a particular embodiment, R¹³ is aC₁₋₄alkylene-C(O)NH₂ group or C₁₋₄alkylene-C(O)N(alkyl)₂ group.

In still another embodiment of the compounds of Formula IIC, R¹³ is—CH₂OH, —CH₂CH₂NHC(O)CH₃ or

In another embodiment, the compounds of the present invention, orpharmaceutically acceptable salts, solvates, stereoisomers and/or estersthereof, have the following structure IID:

wherein,

-   L¹ is selected from the group consisting of —C(R⁶)₂—, —C(O)—,    —S(O₂)—, —N(R⁷)—C(O)—, and —O—C(O)—;-   each L³ is independently a covalent bond, an alkylene, or    substituted alkylene;-   each L⁴ is independently selected from the group consisting of a    covalent bond, alkylene, substituted alkylene, —O—, —CH₂—O—, and    —NH—;-   each A is independently selected from the group consisting of H,    alkyl, substituted alkyl, aryl, substituted aryl, heterocyclyl, and    substituted heterocyclyl,    -   with the proviso that when A is H, p is 0;-   Z¹ and Z² are each independently —O— or —N(R⁷)—;-   Y and X are independently selected from the group consisting of    heterocyclyl and heterocyclylalkyl;-   each Ar is independently selected from the group consisting of aryl,    substituted aryl, heteroaryl, and substituted heteroaryl;-   R¹, R³, and R⁵ are each independently selected from the group    consisting of H, alkyl, substituted alkyl, arylalkyl, and    substituted arylalkyl;-   R² is independently selected from the group consisting of H, alkyl,    substituted alkyl, alkoxyalkyl, hydroxyalkyl, arylheteroalkyl,    substituted arylheteroalkyl, arylalkyl, substituted arylalkyl,    heterocyclylalkyl, substituted heterocyclylalkyl, aminoalkyl,    substituted aminoalkyl, -alkylene-C(O)—OH, -alkylene-C(O)—Oalkyl,    -alkylene-C(O)amino, -alkylene-C(O)-alkyl;-   R⁴ and R⁶ are independently selected from the group consisting of H,    alkyl, substituted alkyl, and heteroalkyl;-   each R⁷ is independently selected from the group consisting of H,    alkyl, substituted alkyl, heteroalkyl, carbocyclyl, substituted    carbocyclyl, heterocyclyl, and substituted heterocyclyl;-   R⁸ and R⁹ are each one or more substituents independently selected    from the group consisting of H, alkyl, substituted alkyl, halogen,    aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, and    —CN; and    -   each p is independently 0 or 1.

In another embodiment of the compounds of Formula IID, L¹ is —C(R⁶)₂—.

In another embodiment of the compounds of Formula IID, L¹ is —CH₂—.

In another embodiment of the compounds of Formula IID, each L³ isalkylene.

In another embodiment of the compounds of Formula IID, each L³ is —CH₂—.

In another embodiment of the compounds of Formula IID, each A is aryl orsubstituted aryl.

In another embodiment of the compounds of Formula IID, each A is phenylor substituted phenyl.

In another embodiment of the compounds of Formula IID, X isheterocyclylalkyl.

In another embodiment of the compounds of Formula IID, X isthiazolylmethyl.

In another embodiment of the compounds of Formula IID, Y isheterocyclylalkyl.

In another embodiment of the compounds of Formula IID, Y isthiazolylmethyl.

In another embodiment of the compounds of Formula IID, Z¹ is —N(R⁷)—.

In another embodiment of the compounds of Formula IID, Z¹ is —NH—.

In another embodiment of the compounds of Formula IID, Z¹ is —N(alkyl)-.

In another embodiment of the compounds of Formula IID, Z¹ is —N(CH₃)—.

In another embodiment of the compounds of Formula IID, Z² is —O—.

In another embodiment of the compounds of Formula IID, L¹ is —C(R⁶)₂—and X and Y are heterocyclylalkyl.

In another embodiment of the compounds of Formula IID, L¹ is —CH₂— and Xand Y are heterocyclylalkyl.

In another embodiment of the compounds of Formula IID, L¹ is —CH₂— and Xand Y are thiazolylmethyl.

In another embodiment of the compounds of Formula IID, L¹ is —C(R⁶)₂—and Z¹ is —N(R⁷)—.

In another embodiment of the compounds of Formula IID, L¹ is —CH₂— andZ¹ is —N(R⁷)—.

In another embodiment of the compounds of Formula IID, L¹ is —CH₂— andZ¹ is —NH—.

In another embodiment of the compounds of Formula IID, L¹ is —CH₂— andZ¹ is —N(alkyl)-.

In another embodiment of the compounds of Formula IID, L¹ is —CH₂— andZ¹ is —N(CH₃)—.

In another embodiment of the compounds of Formula IID, L¹ is —C(R⁶)₂—and Z² is —O—.

In another embodiment of the compounds of Formula IID, each L³ isalkylene and each A is aryl or substituted aryl.

In another embodiment of the compounds of Formula IID, each L³ is —CH₂—and each A is aryl or substituted aryl.

In another embodiment of the compounds of Formula IID, each L³-A isbenzyl or substituted benzyl.

In another embodiment of the compounds of Formula IID, X and Y areheterocyclylalkyl and Z¹ is —N(R⁷)—.

In another embodiment of the compounds of Formula IID, X and Y arethiazolylmethyl and Z¹ is —N(R⁷)—.

In another embodiment of the compounds of Formula IID, X and Y arethiazolylmethyl and Z¹ is —N(alkyl)-.

In another embodiment of the compounds of Formula IID, X and Y arethiazolylmethyl and Z¹ is —N(CH₃)—.

In another embodiment of the compounds of Formula IID, X and Y arethiazolylmethyl and Z¹ is —NH—.

In another embodiment of the compounds of Formula IID, X and Y areheterocyclylalkyl and Z² is —O—.

In another embodiment of the compounds of Formula IID, X and Y arethiazolylmethyl and Z² is —O—.

In another embodiment of the compounds of Formula IID, Z¹ is —N(R⁷)— andZ² is —O—.

In another embodiment of the compounds of Formula IID, Z¹ is —N(alkyl)-and Z² is —O—.

In another embodiment of the compounds of Formula IID, Z¹ is —N(CH₃)—and Z² is —O—.

In another embodiment of the compounds of Formula IID, Z¹ is —NH— and Z²is —O—.

In another embodiment of the compounds of Formula IID, L¹ is —C(R⁶)₂—, Xand Y are heterocyclylalkyl, and Z¹ is —N(R⁷)—.

In another embodiment of the compounds of Formula IID, L¹ is —CH₂—, Xand Y are heterocyclylalkyl, and Z¹ is —N(R⁷)—.

In another embodiment of the compounds of Formula IID, L¹ is —CH₂—, Xand Y are thiazolylmethyl, and Z¹ is —N(R⁷)—.

In another embodiment of the compounds of Formula IID, L¹ is —CH₂—, Xand Y are thiazolylmethyl, and Z¹ is —N(alkyl)-.

In another embodiment of the compounds of Formula IID, L¹ is —CH₂—, Xand Y are thiazolylmethyl, and Z¹ is —N(CH₃)—.

In another embodiment of the compounds of Formula IID, L¹ is —CH₂—, Xand Y are thiazolylmethyl, and Z¹ is —NH—.

In another embodiment of the compounds of Formula IID, L¹ is —C(R⁶)₂—; Xand Y are heterocyclylalkyl; and Z² is —O—.

In another embodiment of the compounds of Formula IID, L¹ is —CH₂—; Xand Y are heterocyclylalkyl; and Z² is —O—.

In another embodiment of the compounds of Formula IID, L¹ is —CH₂—; Xand Y are thiazolylmethyl; and Z² is —O—.

In another embodiment of the compounds of Formula IID, L¹ is —C(R⁶)₂—;each L³ is alkylene; each A is aryl or substituted aryl; X and Y areheterocyclylalkyl; Z¹ is —N(R⁷)—; and Z² is —O—.

In another embodiment of the compounds of Formula IID, L¹ is —CH₂—; eachL³-A is benzyl or substituted benzyl; X and Y are thiazolylmethyl; Z¹ is—N(CH₃)—; and Z² is —O—.

In another embodiment of the compounds of Formula IID, L¹ is —CH₂—; eachL³-A is benzyl or substituted benzyl; Z¹ is —N(CH₃)—; Z² is —O—; X is

In still yet another embodiment, the compounds of Formula I are namedbelow in tabular format (Table 6) as compounds of general Formula II:

Compounds of general formula II are depicted as a “core” structure (Z)substituted with four moieties T1, T2, X1 and X2. The core structures Zare depicted in Table 1. The points of attachment of T1, T2, X1 and X2are indicated on each of the core structures depicted in Table 1. Tables2-5, respectively, show the structures of the T1, T2, X1 and X2moieties. The point of attachment of the core structure Z is indicatedin each of the structures of T1, T2, X1 and X2. Each core structure Z inTable 1, and each substituent T1, T2, X1 and X2 and Tables 2-5 isrepresented by a “code” comprising a letter and a number. Each structureof a compound of Formula II can be designated in tabular form bycombining the “code” representing each structural moiety using thefollowing syntax: Z.T1.T2.X1.X2. Thus, for example, Z¹.T1A.T2B.X1A.X2Arepresents the following structure:

In the structures depicted in Tables 1-5, the term “Alk” means asubstituted or unsubstituted alkyl, cycloalkyl, or alkylene group,wherein the terms “alkyl”, “cycloalkyl”, and “alkylene” are as definedherein. “Alk” means an alkyl or cycloalkyl group when depicted asmonovalent, and an alkylene group when depicted as divalent. “Het” is asubstituted or unsubstituted heterocyclyl or heterocyclylene group,wherein the term “heterocyclyl” is as defined herein, and the term“heterocyclylene” means a heterocyclyl group as defined herein, in whicha hydrogen atom has been replaced by an open valence (in analogy toalkylene), thereby defining a divalent heterocyclyl. “Het” is aheterocyclyl when depicted as monovalent, and heterocyclylene whendepicted as divalent. “Ar” is a substitute or unsubstituted aryl orarylene group, wherein the term “aryl” is as defined herein, and theterm “arylene” means an aryl group as defined herein, in which ahydrogen atom has been replaced by an open valence (in analogy toalkylene), thereby defining a divalent aryl. “Ar” is aryl when depictedas monovalent, and arylene when depicted as divalent. When substituted,“Alk”, “Het”, and “Ar” can be substituted with any of the substituentsdefined or exemplified herein. For example, substituents of “Alk” caninclude ether, halogen, —OH, amide, amine, etc., substituents of “Het”can include alkyl, aryl, carbonyl, —OH, halogen, and substituents of“Ar” can include alkyl aryl, —OH, halogen, etc., with the proviso thatthe resulting structure is chemically reasonable, and would providecompounds which are sufficiently stable for formulation in apharmaceutically acceptable composition. When a structure orsubstructure shown in the tables below contains more than one “Alk”,“Het” or “Ar” group, these groups are independently selected and can bethe same or different. So, for example, each of the “Alk” groups ofsubstructure T1A are independently selected and may be the same ordifferent.

TABLE 1 Core Structures Code Core Structure Z1

Z2

Z3

Z4

Z5

Z6

TABLE 2 T1 Structures Code T1 Structure T1A

T1B

T1C

T1D

TABLE 3 T2 Structures Code T2 Structure T2A —O-Alk-Het T2B —NH-Alk-HetT2C —N(Alk)-Alk-Het T2D —N(Alk)-Het

TABLE 4 X1 Structures Code X1 Structure X1A -Alk X1B -Alk-Ar X1C-Alk-Het X1D -Alk-Ar—O-Alk-Ar X1E -Alk-Ar—O-Alk-Het

TABLE 5 X2 Structures Code X2 Structure X2A -Alk X2B -Alk-Ar X2C-Alk-Het X2D -Alk-Ar—O-Alk-Ar X2E -Alk-Ar—O-Alk-Het

TABLE 6 List of Compound Structures of Formula II Z1.T1A.T2A.X1A.X2A,Z2.T1A.T2A.X1A.X2A, Z3.T1A.T2A.X1A.X2A, Z4.T1A.T2A.X1A.X2A,Z5.T1A.T2A.X1A.X2A, Z6.T1A.T2A.X1A.X2A, Z1.T1B.T2A.X1A.X2A,Z2.T1B.T2A.X1A.X2A, Z3.T1B.T2A.X1A.X2A, Z4.T1B.T2A.X1A.X2A,Z5.T1B.T2A.X1A.X2A, Z6.T1B.T2A.X1A.X2A, Z1.T1C.T2A.X1A.X2A,Z2.T1C.T2A.X1A.X2A, Z3.T1C.T2A.X1A.X2A, Z4.T1C.T2A.X1A.X2A,Z5.T1C.T2A.X1A.X2A, Z6.T1C.T2A.X1A.X2A, Z1.T1D.T2A.X1A.X2A,Z2.T1D.T2A.X1A.X2A, Z3.T1D.T2A.X1A.X2A, Z4.T1D.T2A.X1A.X2A,Z5.T1D.T2A.X1A.X2A, Z6.T1D.T2A.X1A.X2A, Z1.T1A.T2B.X1A.X2A,Z2.T1A.T2B.X1A.X2A, Z3.T1A.T2B.X1A.X2A, Z4.T1A.T2B.X1A.X2A,Z5.T1A.T2B.X1A.X2A, Z6.T1A.T2B.X1A.X2A, Z1.T1B.T2B.X1A.X2A,Z2.T1B.T2B.X1A.X2A, Z3.T1B.T2B.X1A.X2A, Z4.T1B.T2B.X1A.X2A,Z5.T1B.T2B.X1A.X2A, Z6.T1B.T2B.X1A.X2A, Z1.T1C.T2B.X1A.X2A,Z2.T1C.T2B.X1A.X2A, Z3.T1C.T2B.X1A.X2A, Z4.T1C.T2B.X1A.X2A,Z5.T1C.T2B.X1A.X2A, Z6.T1C.T2B.X1A.X2A, Z1.T1D.T2B.X1A.X2A,Z2.T1D.T2B.X1A.X2A, Z3.T1D.T2B.X1A.X2A, Z4.T1D.T2B.X1A.X2A,Z5.T1D.T2B.X1A.X2A, Z6.T1D.T2B.X1A.X2A, Z1.T1A.T2C.X1A.X2A,Z2.T1A.T2C.X1A.X2A, Z3.T1A.T2C.X1A.X2A, Z4.T1A.T2C.X1A.X2A,Z5.T1A.T2C.X1A.X2A, Z6.T1A.T2C.X1A.X2A, Z1.T1B.T2C.X1A.X2A,Z2.T1B.T2C.X1A.X2A, Z3.T1B.T2C.X1A.X2A, Z4.T1B.T2C.X1A.X2A,Z5.T1B.T2C.X1A.X2A, Z6.T1B.T2C.X1A.X2A, Z1.T1C.T2C.X1A.X2A,Z2.T1C.T2C.X1A.X2A, Z3.T1C.T2C.X1A.X2A, Z4.T1C.T2C.X1A.X2A,Z5.T1C.T2C.X1A.X2A, Z6.T1C.T2C.X1A.X2A, Z1.T1D.T2C.X1A.X2A,Z2.T1D.T2C.X1A.X2A, Z3.T1D.T2C.X1A.X2A, Z4.T1D.T2C.X1A.X2A,Z5.T1D.T2C.X1A.X2A, Z6.T1D.T2C.X1A.X2A, Z1.T1A.T2D.X1A.X2A,Z2.T1A.T2D.X1A.X2A, Z3.T1A.T2D.X1A.X2A, Z4.T1A.T2D.X1A.X2A,Z5.T1A.T2D.X1A.X2A, Z6.T1A.T2D.X1A.X2A, Z1.T1B.T2D.X1A.X2A,Z2.T1B.T2D.X1A.X2A, Z3.T1B.T2D.X1A.X2A, Z4.T1B.T2D.X1A.X2A,Z5.T1B.T2D.X1A.X2A, Z6.T1B.T2D.X1A.X2A, Z1.T1C.T2D.X1A.X2A,Z2.T1C.T2D.X1A.X2A, Z3.T1C.T2D.X1A.X2A, Z4.T1C.T2D.X1A.X2A,Z5.T1C.T2D.X1A.X2A, Z6.T1C.T2D.X1A.X2A, Z1.T1D.T2D.X1A.X2A,Z2.T1D.T2D.X1A.X2A, Z3.T1D.T2D.X1A.X2A, Z4.T1D.T2D.X1A.X2A,Z5.T1D.T2D.X1A.X2A, Z6.T1D.T2D.X1A.X2A, Z1.T1A.T2A.X1B.X2A,Z2.T1A.T2A.X1B.X2A, Z3.T1A.T2A.X1B.X2A, Z4.T1A.T2A.X1B.X2A,Z5.T1A.T2A.X1B.X2A, Z6.T1A.T2A.X1B.X2A, Z1.T1B.T2A.X1B.X2A,Z2.T1B.T2A.X1B.X2A, Z3.T1B.T2A.X1B.X2A, Z4.T1B.T2A.X1B.X2A,Z5.T1B.T2A.X1B.X2A, Z6.T1B.T2A.X1B.X2A, Z1.T1C.T2A.X1B.X2A,Z2.T1C.T2A.X1B.X2A, Z3.T1C.T2A.X1B.X2A, Z4.T1C.T2A.X1B.X2A,Z5.T1C.T2A.X1B.X2A, Z6.T1C.T2A.X1B.X2A, Z1.T1D.T2A.X1B.X2A,Z2.T1D.T2A.X1B.X2A, Z3.T1D.T2A.X1B.X2A, Z4.T1D.T2A.X1B.X2A,Z5.T1D.T2A.X1B.X2A, Z6.T1D.T2A.X1B.X2A, Z1.T1A.T2B.X1B.X2A,Z2.T1A.T2B.X1B.X2A, Z3.T1A.T2B.X1B.X2A, Z4.T1A.T2B.X1B.X2A,Z5.T1A.T2B.X1B.X2A, Z6.T1A.T2B.X1B.X2A, Z1.T1B.T2B.X1B.X2A,Z2.T1B.T2B.X1B.X2A, Z3.T1B.T2B.X1B.X2A, Z4.T1B.T2B.X1B.X2A,Z5.T1B.T2B.X1B.X2A, Z6.T1B.T2B.X1B.X2A, Z1.T1C.T2B.X1B.X2A,Z2.T1C.T2B.X1B.X2A, Z3.T1C.T2B.X1B.X2A, Z4.T1C.T2B.X1B.X2A,Z5.T1C.T2B.X1B.X2A, Z6.T1C.T2B.X1B.X2A, Z1.T1D.T2B.X1B.X2A,Z2.T1D.T2B.X1B.X2A, Z3.T1D.T2B.X1B.X2A, Z4.T1D.T2B.X1B.X2A,Z5.T1D.T2B.X1B.X2A, Z6.T1D.T2B.X1B.X2A, Z1.T1A.T2C.X1B.X2A,Z2.T1A.T2C.X1B.X2A, Z3.T1A.T2C.X1B.X2A, Z4.T1A.T2C.X1B.X2A,Z5.T1A.T2C.X1B.X2A, Z6.T1A.T2C.X1B.X2A, Z1.T1B.T2C.X1B.X2A,Z2.T1B.T2C.X1B.X2A, Z3.T1B.T2C.X1B.X2A, Z4.T1B.T2C.X1B.X2A,Z5.T1B.T2C.X1B.X2A, Z6.T1B.T2C.X1B.X2A, Z1.T1C.T2C.X1B.X2A,Z2.T1C.T2C.X1B.X2A, Z3.T1C.T2C.X1B.X2A, Z4.T1C.T2C.X1B.X2A,Z5.T1C.T2C.X1B.X2A, Z6.T1C.T2C.X1B.X2A, Z1.T1D.T2C.X1B.X2A,Z2.T1D.T2C.X1B.X2A, Z3.T1D.T2C.X1B.X2A, Z4.T1D.T2C.X1B.X2A,Z5.T1D.T2C.X1B.X2A, Z6.T1D.T2C.X1B.X2A, Z1.T1A.T2D.X1B.X2A,Z2.T1A.T2D.X1B.X2A, Z3.T1A.T2D.X1B.X2A, Z4.T1A.T2D.X1B.X2A,Z5.T1A.T2D.X1B.X2A, Z6.T1A.T2D.X1B.X2A, Z1.T1B.T2D.X1B.X2A,Z2.T1B.T2D.X1B.X2A, Z3.T1B.T2D.X1B.X2A, Z4.T1B.T2D.X1B.X2A,Z5.T1B.T2D.X1B.X2A, Z6.T1B.T2D.X1B.X2A, Z1.T1C.T2D.X1B.X2A,Z2.T1C.T2D.X1B.X2A, Z3.T1C.T2D.X1B.X2A, Z4.T1C.T2D.X1B.X2A,Z5.T1C.T2D.X1B.X2A, Z6.T1C.T2D.X1B.X2A, Z1.T1D.T2D.X1B.X2A,Z2.T1D.T2D.X1B.X2A, Z3.T1D.T2D.X1B.X2A, Z4.T1D.T2D.X1B.X2A,Z5.T1D.T2D.X1B.X2A, Z6.T1D.T2D.X1B.X2A, Z1.T1A.T2A.X1C.X2A,Z2.T1A.T2A.X1C.X2A, Z3.T1A.T2A.X1C.X2A, Z4.T1A.T2A.X1C.X2A,Z5.T1A.T2A.X1C.X2A, Z6.T1A.T2A.X1C.X2A, Z1.T1B.T2A.X1C.X2A,Z2.T1B.T2A.X1C.X2A, Z3.T1B.T2A.X1C.X2A, Z4.T1B.T2A.X1C.X2A,Z5.T1B.T2A.X1C.X2A, Z6.T1B.T2A.X1C.X2A, Z1.T1C.T2A.X1C.X2A,Z2.T1C.T2A.X1C.X2A, Z3.T1C.T2A.X1C.X2A, Z4.T1C.T2A.X1C.X2A,Z5.T1C.T2A.X1C.X2A, Z6.T1C.T2A.X1C.X2A, Z1.T1D.T2A.X1C.X2A,Z2.T1D.T2A.X1C.X2A, Z3.T1D.T2A.X1C.X2A, Z4.T1D.T2A.X1C.X2A,Z5.T1D.T2A.X1C.X2A, Z6.T1D.T2A.X1C.X2A, Z1.T1A.T2B.X1C.X2A,Z2.T1A.T2B.X1C.X2A, Z3.T1A.T2B.X1C.X2A, Z4.T1A.T2B.X1C.X2A,Z5.T1A.T2B.X1C.X2A, Z6.T1A.T2B.X1C.X2A, Z1.T1B.T2B.X1C.X2A,Z2.T1B.T2B.X1C.X2A, Z3.T1B.T2B.X1C.X2A, Z4.T1B.T2B.X1C.X2A,Z5.T1B.T2B.X1C.X2A, Z6.T1B.T2B.X1C.X2A, Z1.T1C.T2B.X1C.X2A,Z2.T1C.T2B.X1C.X2A, Z3.T1C.T2B.X1C.X2A, Z4.T1C.T2B.X1C.X2A,Z5.T1C.T2B.X1C.X2A, Z6.T1C.T2B.X1C.X2A, Z1.T1D.T2B.X1C.X2A,Z2.T1D.T2B.X1C.X2A, Z3.T1D.T2B.X1C.X2A, Z4.T1D.T2B.X1C.X2A,Z5.T1D.T2B.X1C.X2A, Z6.T1D.T2B.X1C.X2A, Z1.T1A.T2C.X1C.X2A,Z2.T1A.T2C.X1C.X2A, Z3.T1A.T2C.X1C.X2A, Z4.T1A.T2C.X1C.X2A,Z5.T1A.T2C.X1C.X2A, Z6.T1A.T2C.X1C.X2A, 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Z1.T1D.T2A.X1D.X2E,Z2.T1D.T2A.X1D.X2E, Z3.T1D.T2A.X1D.X2E, Z4.T1D.T2A.X1D.X2E,Z5.T1D.T2A.X1D.X2E, Z6.T1D.T2A.X1D.X2E, Z1.T1A.T2B.X1D.X2E,Z2.T1A.T2B.X1D.X2E, Z3.T1A.T2B.X1D.X2E, Z4.T1A.T2B.X1D.X2E,Z5.T1A.T2B.X1D.X2E, Z6.T1A.T2B.X1D.X2E, Z1.T1B.T2B.X1D.X2E,Z2.T1B.T2B.X1D.X2E, Z3.T1B.T2B.X1D.X2E, Z4.T1B.T2B.X1D.X2E,Z5.T1B.T2B.X1D.X2E, Z6.T1B.T2B.X1D.X2E, Z1.T1C.T2B.X1D.X2E,Z2.T1C.T2B.X1D.X2E, Z3.T1C.T2B.X1D.X2E, Z4.T1C.T2B.X1D.X2E,Z5.T1C.T2B.X1D.X2E, Z6.T1C.T2B.X1D.X2E, Z1.T1D.T2B.X1D.X2E,Z2.T1D.T2B.X1D.X2E, Z3.T1D.T2B.X1D.X2E, Z4.T1D.T2B.X1D.X2E,Z5.T1D.T2B.X1D.X2E, Z6.T1D.T2B.X1D.X2E, Z1.T1A.T2C.X1D.X2E,Z2.T1A.T2C.X1D.X2E, Z3.T1A.T2C.X1D.X2E, Z4.T1A.T2C.X1D.X2E,Z5.T1A.T2C.X1D.X2E, Z6.T1A.T2C.X1D.X2E, Z1.T1B.T2C.X1D.X2E,Z2.T1B.T2C.X1D.X2E, Z3.T1B.T2C.X1D.X2E, Z4.T1B.T2C.X1D.X2E,Z5.T1B.T2C.X1D.X2E, Z6.T1B.T2C.X1D.X2E, Z1.T1C.T2C.X1D.X2E,Z2.T1C.T2C.X1D.X2E, Z3.T1C.T2C.X1D.X2E, Z4.T1C.T2C.X1D.X2E,Z5.T1C.T2C.X1D.X2E, Z6.T1C.T2C.X1D.X2E, Z1.T1D.T2C.X1D.X2E,Z2.T1D.T2C.X1D.X2E, Z3.T1D.T2C.X1D.X2E, Z4.T1D.T2C.X1D.X2E,Z5.T1D.T2C.X1D.X2E, Z6.T1D.T2C.X1D.X2E, Z1.T1A.T2D.X1D.X2E,Z2.T1A.T2D.X1D.X2E, Z3.T1A.T2D.X1D.X2E, Z4.T1A.T2D.X1D.X2E,Z5.T1A.T2D.X1D.X2E, Z6.T1A.T2D.X1D.X2E, Z1.T1B.T2D.X1D.X2E,Z2.T1B.T2D.X1D.X2E, Z3.T1B.T2D.X1D.X2E, Z4.T1B.T2D.X1D.X2E,Z5.T1B.T2D.X1D.X2E, Z6.T1B.T2D.X1D.X2E, Z1.T1C.T2D.X1D.X2E,Z2.T1C.T2D.X1D.X2E, Z3.T1C.T2D.X1D.X2E, Z4.T1C.T2D.X1D.X2E,Z5.T1C.T2D.X1D.X2E, Z6.T1C.T2D.X1D.X2E, Z1.T1D.T2D.X1D.X2E,Z2.T1D.T2D.X1D.X2E, Z3.T1D.T2D.X1D.X2E, Z4.T1D.T2D.X1D.X2E,Z5.T1D.T2D.X1D.X2E, Z6.T1D.T2D.X1D.X2E, Z1.T1A.T2A.X1E.X2E,Z2.T1A.T2A.X1E.X2E, Z3.T1A.T2A.X1E.X2E, Z4.T1A.T2A.X1E.X2E,Z5.T1A.T2A.X1E.X2E, Z6.T1A.T2A.X1E.X2E, Z1.T1B.T2A.X1E.X2E,Z2.T1B.T2A.X1E.X2E, Z3.T1B.T2A.X1E.X2E, Z4.T1B.T2A.X1E.X2E,Z5.T1B.T2A.X1E.X2E, Z6.T1B.T2A.X1E.X2E, Z1.T1C.T2A.X1E.X2E,Z2.T1C.T2A.X1E.X2E, Z3.T1C.T2A.X1E.X2E, Z4.T1C.T2A.X1E.X2E,Z5.T1C.T2A.X1E.X2E, Z6.T1C.T2A.X1E.X2E, Z1.T1D.T2A.X1E.X2E,Z2.T1D.T2A.X1E.X2E, Z3.T1D.T2A.X1E.X2E, Z4.T1D.T2A.X1E.X2E,Z5.T1D.T2A.X1E.X2E, Z6.T1D.T2A.X1E.X2E, Z1.T1A.T2B.X1E.X2E,Z2.T1A.T2B.X1E.X2E, Z3.T1A.T2B.X1E.X2E, Z4.T1A.T2B.X1E.X2E,Z5.T1A.T2B.X1E.X2E, Z6.T1A.T2B.X1E.X2E, Z1.T1B.T2B.X1E.X2E,Z2.T1B.T2B.X1E.X2E, Z3.T1B.T2B.X1E.X2E, Z4.T1B.T2B.X1E.X2E,Z5.T1B.T2B.X1E.X2E, Z6.T1B.T2B.X1E.X2E, Z1.T1C.T2B.X1E.X2E,Z2.T1C.T2B.X1E.X2E, Z3.T1C.T2B.X1E.X2E, Z4.T1C.T2B.X1E.X2E,Z5.T1C.T2B.X1E.X2E, Z6.T1C.T2B.X1E.X2E, Z1.T1D.T2B.X1E.X2E,Z2.T1D.T2B.X1E.X2E, Z3.T1D.T2B.X1E.X2E, Z4.T1D.T2B.X1E.X2E,Z5.T1D.T2B.X1E.X2E, Z6.T1D.T2B.X1E.X2E, Z1.T1A.T2C.X1E.X2E,Z2.T1A.T2C.X1E.X2E, Z3.T1A.T2C.X1E.X2E, Z4.T1A.T2C.X1E.X2E,Z5.T1A.T2C.X1E.X2E, Z6.T1A.T2C.X1E.X2E, Z1.T1B.T2C.X1E.X2E,Z2.T1B.T2C.X1E.X2E, Z3.T1B.T2C.X1E.X2E, Z4.T1B.T2C.X1E.X2E,Z5.T1B.T2C.X1E.X2E, Z6.T1B.T2C.X1E.X2E, Z1.T1C.T2C.X1E.X2E,Z2.T1C.T2C.X1E.X2E, Z3.T1C.T2C.X1E.X2E, Z4.T1C.T2C.X1E.X2E,Z5.T1C.T2C.X1E.X2E, Z6.T1C.T2C.X1E.X2E, Z1.T1D.T2C.X1E.X2E,Z2.T1D.T2C.X1E.X2E, Z3.T1D.T2C.X1E.X2E, Z4.T1D.T2C.X1E.X2E,Z5.T1D.T2C.X1E.X2E, Z6.T1D.T2C.X1E.X2E, Z1.T1A.T2D.X1E.X2E,Z2.T1A.T2D.X1E.X2E, Z3.T1A.T2D.X1E.X2E, Z4.T1A.T2D.X1E.X2E,Z5.T1A.T2D.X1E.X2E, Z6.T1A.T2D.X1E.X2E, Z1.T1B.T2D.X1E.X2E,Z2.T1B.T2D.X1E.X2E, Z3.T1B.T2D.X1E.X2E, Z4.T1B.T2D.X1E.X2E,Z5.T1B.T2D.X1E.X2E, Z6.T1B.T2D.X1E.X2E, Z1.T1C.T2D.X1E.X2E,Z2.T1C.T2D.X1E.X2E, Z3.T1C.T2D.X1E.X2E, Z4.T1C.T2D.X1E.X2E,Z5.T1C.T2D.X1E.X2E, Z6.T1C.T2D.X1E.X2E, Z1.T1D.T2D.X1E.X2E,Z2.T1D.T2D.X1E.X2E, Z3.T1D.T2D.X1E.X2E, Z4.T1D.T2D.X1E.X2E,Z5.T1D.T2D.X1E.X2E, and Z6.T1D.T2D.X1E.X2E.

In still another embodiment, selected compounds of Formula I are namedbelow in tabular format (Table 12) as compounds of general Formula III(below):

where 1, 2, 3, 4 and 5 are defined in Tables 7-11, below. Each compoundis designated in tabular form by combining the “code” representing eachstructural moiety using the following syntax: 1.2.3.4.5. Thus, forexample, 1a.2a.3a.4a.5a represents the following structure:

TABLE 7 “1” Structures

Code “1” Structure 1a

1b

1c

1d

1e

1f

1g

1h

1i

1j

1k

1l

1m

1n

1o

1p

1q

1r

1s

1t

1u

TABLE 8 “2” Structures Code “2” Structure 2a

2b

2c

2d

2e

2f

2g

2h

2i

2j

2k

2l

2m

2n

2o

2p

2q

2r

2s

2t

2u

2v

2w

2x

2y

TABLE 9 “3” Structures Code “3” Structure 3a —O—CH₂-(5-thiazolyl) 3b—O—CH₂-(3-pyridyl) 3c —NH—CH₂-(5-thiazolyl) 3d —NH—CH₂-(3-pyridyl) 3e—N(CH₃)—CH₂-(5-thiazolyl) 3f —N(CH₃)—CH₂-(3-pyridyl) 3g—N(CH₃)-(5-thiazolyl) 3h —N(CH₃)-(3-pyridyl)

TABLE 10 “4” Structures Code “4” Structure 4a n-propyl 4b i-butyl 4c—CH₂-cyclohexyl 4d —CH₂-phenyl 4e —CH₂-(4-methoxyphenyl) 4f—CH₂-(3-fluorophenyl) 4g —CH₂-(4-pyridyl) 4h —CH₂-(3-pyridyl) 4i—CH₂-(2-pyridyl) 4j —CH₂CH₂-(4-morpholinyl) 4k

4l

4m

4n

4o

4p

TABLE 11 “5” Structures Code “5” Structure 5a n-propyl 5b i-butyl 5c—CH₂-cyclohexyl 5d —CH₂-phenyl 5e —CH₂-(4-methoxyphenyl) 5f—CH₂-(3-fluorophenyl) 5g —CH₂-(4-pyridyl) 5h —CH₂-(3-pyridyl) 5i—CH₂-(2-pyridyl) 5j —CH₂CH₂-(4-morpholinyl) 5k

5l

5m

5n

5o

TABLE 12 List of Compound Structures of Formula II 1a.2a.3a.4a.5a.,1b.2a.3a.4a.5a., 1f.2a.3a.4a.5a., 1h.2a.3a.4a.5a., 1j.2a.3a.4a.5a.,1p.2a.3a.4a.5a., 1a.2b.3a.4a.5a., 1b.2b.3a.4a.5a., 1f.2b.3a.4a.5a.,1h.2b.3a.4a.5a., 1j.2b.3a.4a.5a., 1p.2b.3a.4a.5a., 1a.2e.3a.4a.5a.,1b.2e.3a.4a.5a., 1f.2e.3a.4a.5a., 1h.2e.3a.4a.5a., 1j.2e.3a.4a.5a.,1p.2e.3a.4a.5a., 1a.2f.3a.4a.5a., 1b.2f.3a.4a.5a., 1f.2f.3a.4a.5a.,1h.2f.3a.4a.5a., 1j.2f.3a.4a.5a., 1p.2f.3a.4a.5a., 1a.2i.3a.4a.5a.,1b.2i.3a.4a.5a., 1f.2i.3a.4a.5a., 1h.2i.3a.4a.5a., 1j.2i.3a.4a.5a.,1p.2i.3a.4a.5a., 1a.2m.3a.4a.5a., 1b.2m.3a.4a.5a., 1f.2m.3a.4a.5a.,1h.2m.3a.4a.5a., 1j.2m.3a.4a.5a., 1p.2m.3a.4a.5a., 1a.2o.3a.4a.5a.,1b.2o.3a.4a.5a., 1f.2o.3a.4a.5a., 1h.2o.3a.4a.5a., 1j.2o.3a.4a.5a.,1p.2o.3a.4a.5a., 1a.2u.3a.4a.5a., 1b.2u.3a.4a.5a., 1f.2u.3a.4a.5a.,1h.2u.3a.4a.5a., 1j.2u.3a.4a.5a., 1p.2u.3a.4a.5a., 1a.2y.3a.4a.5a.,1b.2y.3a.4a.5a., 1f.2y.3a.4a.5a., 1h.2y.3a.4a.5a., 1j.2y.3a.4a.5a.,1p.2y.3a.4a.5a., 1a.2a.3b.4a.5a., 1b.2a.3b.4a.5a., 1f.2a.3b.4a.5a.,1h.2a.3b.4a.5a., 1j.2a.3b.4a.5a., 1p.2a.3b.4a.5a., 1a.2b.3b.4a.5a.,1b.2b.3b.4a.5a., 1f.2b.3b.4a.5a., 1h.2b.3b.4a.5a., 1j.2b.3b.4a.5a.,1p.2b.3b.4a.5a., 1a.2e.3b.4a.5a., 1b.2e.3b.4a.5a., 1f.2e.3b.4a.5a.,1h.2e.3b.4a.5a., 1j.2e.3b.4a.5a., 1p.2e.3b.4a.5a., 1a.2f.3b.4a.5a.,1b.2f.3b.4a.5a., 1f.2f.3b.4a.5a., 1h.2f.3b.4a.5a., 1j.2f.3b.4a.5a.,1p.2f.3b.4a.5a., 1a.2i.3b.4a.5a., 1b.2i.3b.4a.5a., 1f.2i.3b.4a.5a.,1h.2i.3b.4a.5a., 1j.2i.3b.4a.5a., 1p.2i.3b.4a.5a., 1a.2m.3b.4a.5a.,1b.2m.3b.4a.5a., 1f.2m.3b.4a.5a., 1h.2m.3b.4a.5a., 1j.2m.3b.4a.5a.,1p.2m.3b.4a.5a., 1a.2o.3b.4a.5a., 1b.2o.3b.4a.5a., 1f.2o.3b.4a.5a.,1h.2o.3b.4a.5a., 1j.2o.3b.4a.5a., 1p.2o.3b.4a.5a., 1a.2u.3b.4a.5a.,1b.2u.3b.4a.5a., 1f.2u.3b.4a.5a., 1h.2u.3b.4a.5a., 1j.2u.3b.4a.5a.,1p.2u.3b.4a.5a., 1a.2y.3b.4a.5a., 1b.2y.3b.4a.5a., 1f.2y.3b.4a.5a.,1h.2y.3b.4a.5a., 1j.2y.3b.4a.5a., 1p.2y.3b.4a.5a., 1a.2a.3e.4a.5a.,1b.2a.3e.4a.5a., 1f.2a.3e.4a.5a., 1h.2a.3e.4a.5a., 1j.2a.3e.4a.5a.,1p.2a.3e.4a.5a., 1a.2b.3e.4a.5a., 1b.2b.3e.4a.5a., 1f.2b.3e.4a.5a.,1h.2b.3e.4a.5a., 1j.2b.3e.4a.5a., 1p.2b.3e.4a.5a., 1a.2e.3e.4a.5a.,1b.2e.3e.4a.5a., 1f.2e.3e.4a.5a., 1h.2e.3e.4a.5a., 1j.2e.3e.4a.5a.,1p.2e.3e.4a.5a., 1a.2f.3e.4a.5a., 1b.2f.3e.4a.5a., 1f.2f.3e.4a.5a.,1h.2f.3e.4a.5a., 1j.2f.3e.4a.5a., 1p.2f.3e.4a.5a., 1a.2i.3e.4a.5a.,1b.2i.3e.4a.5a., 1f.2i.3e.4a.5a., 1h.2i.3e.4a.5a., 1j.2i.3e.4a.5a.,1p.2i.3e.4a.5a., 1a.2m.3e.4a.5a., 1b.2m.3e.4a.5a., 1f.2m.3e.4a.5a.,1h.2m.3e.4a.5a., 1j.2m.3e.4a.5a., 1p.2m.3e.4a.5a., 1a.2o.3e.4a.5a.,1b.2o.3e.4a.5a., 1f.2o.3e.4a.5a., 1h.2o.3e.4a.5a., 1j.2o.3e.4a.5a.,1p.2o.3e.4a.5a., 1a.2u.3e.4a.5a., 1b.2u.3e.4a.5a., 1f.2u.3e.4a.5a.,1h.2u.3e.4a.5a., 1j.2u.3e.4a.5a., 1p.2u.3e.4a.5a., 1a.2y.3e.4a.5a.,1b.2y.3e.4a.5a., 1f.2y.3e.4a.5a., 1h.2y.3e.4a.5a., 1j.2y.3e.4a.5a.,1p.2y.3e.4a.5a., 1a.2a.3g.4a.5a., 1b.2a.3g.4a.5a., 1f.2a.3g.4a.5a.,1h.2a.3g.4a.5a., 1j.2a.3g.4a.5a., 1p.2a.3g.4a.5a., 1a.2b.3g.4a.5a.,1b.2b.3g.4a.5a., 1f.2b.3g.4a.5a., 1h.2b.3g.4a.5a., 1j.2b.3g.4a.5a.,1p.2b.3g.4a.5a., 1a.2e.3g.4a.5a., 1b.2e.3g.4a.5a., 1f.2e.3g.4a.5a.,1h.2e.3g.4a.5a., 1j.2e.3g.4a.5a., 1p.2e.3g.4a.5a., 1a.2f.3g.4a.5a.,1b.2f.3g.4a.5a., 1f.2f.3g.4a.5a., 1h.2f.3g.4a.5a., 1j.2f.3g.4a.5a.,1p.2f.3g.4a.5a., 1a.2i.3g.4a.5a., 1b.2i.3g.4a.5a., 1f.2i.3g.4a.5a.,1h.2i.3g.4a.5a., 1j.2i.3g.4a.5a., 1p.2i.3g.4a.5a., 1a.2m.3g.4a.5a.,1b.2m.3g.4a.5a., 1f.2m.3g.4a.5a., 1h.2m.3g.4a.5a., 1j.2m.3g.4a.5a.,1p.2m.3g.4a.5a., 1a.2o.3g.4a.5a., 1b.2o.3g.4a.5a., 1f.2o.3g.4a.5a.,1h.2o.3g.4a.5a., 1j.2o.3g.4a.5a., 1p.2o.3g.4a.5a., 1a.2u.3g.4a.5a.,1b.2u.3g.4a.5a., 1f.2u.3g.4a.5a., 1h.2u.3g.4a.5a., 1j.2u.3g.4a.5a.,1p.2u.3g.4a.5a., 1a.2y.3g.4a.5a., 1b.2y.3g.4a.5a., 1f.2y.3g.4a.5a.,1h.2y.3g.4a.5a., 1j.2y.3g.4a.5a., 1p.2y.3g.4a.5a., 1a.2a.3a.4d.5a.,1b.2a.3a.4d.5a., 1f.2a.3a.4d.5a., 1h.2a.3a.4d.5a., 1j.2a.3a.4d.5a.,1p.2a.3a.4d.5a., 1a.2b.3a.4d.5a., 1b.2b.3a.4d.5a., 1f.2b.3a.4d.5a.,1h.2b.3a.4d.5a., 1j.2b.3a.4d.5a., 1p.2b.3a.4d.5a., 1a.2e.3a.4d.5a.,1b.2e.3a.4d.5a., 1f.2e.3a.4d.5a., 1h.2e.3a.4d.5a., 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1j.2b.3b.4i.5i.,1p.2b.3b.4i.5i., 1a.2e.3b.4i.5i., 1b.2e.3b.4i.5i., 1f.2e.3b.4i.5i.,1h.2e.3b.4i.5i., 1j.2e.3b.4i.5i., 1p.2e.3b.4i.5i., 1a.2f.3b.4i.5i.,1b.2f.3b.4i.5i., 1f.2f.3b.4i.5i., 1h.2f.3b.4i.5i., 1j.2f.3b.4i.5i.,1p.2f.3b.4i.5i., 1a.2i.3b.4i.5i., 1b.2i.3b.4i.5i., 1f.2i.3b.4i.5i.,1h.2i.3b.4i.5i., 1j.2i.3b.4i.5i., 1p.2i.3b.4i.5i., 1a.2m.3b.4i.5i.,1b.2m.3b.4i.5i., 1f.2m.3b.4i.5i., 1h.2m.3b.4i.5i., 1j.2m.3b.4i.5i.,1p.2m.3b.4i.5i., 1a.2o.3b.4i.5i., 1b.2o.3b.4i.5i., 1f.2o.3b.4i.5i.,1h.2o.3b.4i.5i., 1j.2o.3b.4i.5i., 1p.2o.3b.4i.5i., 1a.2u.3b.4i.5i.,1b.2u.3b.4i.5i., 1f.2u.3b.4i.5i., 1h.2u.3b.4i.5i., 1j.2u.3b.4i.5i.,1p.2u.3b.4i.5i., 1a.2y.3b.4i.5i., 1b.2y.3b.4i.5i., 1f.2y.3b.4i.5i.,1h.2y.3b.4i.5i., 1j.2y.3b.4i.5i., 1p.2y.3b.4i.5i., 1a.2a.3e.4i.5i.,1b.2a.3e.4i.5i., 1f.2a.3e.4i.5i., 1h.2a.3e.4i.5i., 1j.2a.3e.4i.5i.,1p.2a.3e.4i.5i., 1a.2b.3e.4i.5i., 1b.2b.3e.4i.5i., 1f.2b.3e.4i.5i.,1h.2b.3e.4i.5i., 1j.2b.3e.4i.5i., 1p.2b.3e.4i.5i., 1a.2e.3e.4i.5i.,1b.2e.3e.4i.5i., 1f.2e.3e.4i.5i., 1h.2e.3e.4i.5i., 1j.2e.3e.4i.5i.,1p.2e.3e.4i.5i., 1a.2f.3e.4i.5i., 1b.2f.3e.4i.5i., 1f.2f.3e.4i.5i.,1h.2f.3e.4i.5i., 1j.2f.3e.4i.5i., 1p.2f.3e.4i.5i., 1a.2i.3e.4i.5i.,1b.2i.3e.4i.5i., 1f.2i.3e.4i.5i., 1h.2i.3e.4i.5i., 1j.2i.3e.4i.5i.,1p.2i.3e.4i.5i., 1a.2m.3e.4i.5i., 1b.2m.3e.4i.5i., 1f.2m.3e.4i.5i.,1h.2m.3e.4i.5i., 1j.2m.3e.4i.5i., 1p.2m.3e.4i.5i., 1a.2o.3e.4i.5i.,1b.2o.3e.4i.5i., 1f.2o.3e.4i.5i., 1h.2o.3e.4i.5i., 1j.2o.3e.4i.5i.,1p.2o.3e.4i.5i., 1a.2u.3e.4i.5i., 1b.2u.3e.4i.5i., 1f.2u.3e.4i.5i.,1h.2u.3e.4i.5i., 1j.2u.3e.4i.5i., 1p.2u.3e.4i.5i., 1a.2y.3e.4i.5i.,1b.2y.3e.4i.5i., 1f.2y.3e.4i.5i., 1h.2y.3e.4i.5i., 1j.2y.3e.4i.5i.,1p.2y.3e.4i.5i., 1a.2a.3g.4i.5i., 1b.2a.3g.4i.5i., 1f.2a.3g.4i.5i.,1h.2a.3g.4i.5i., 1j.2a.3g.4i.5i., 1p.2a.3g.4i.5i., 1a.2b.3g.4i.5i.,1b.2b.3g.4i.5i., 1f.2b.3g.4i.5i., 1h.2b.3g.4i.5i., 1j.2b.3g.4i.5i.,1p.2b.3g.4i.5i., 1a.2e.3g.4i.5i., 1b.2e.3g.4i.5i., 1f.2e.3g.4i.5i.,1h.2e.3g.4i.5i., 1j.2e.3g.4i.5i., 1p.2e.3g.4i.5i., 1a.2f.3g.4i.5i.,1b.2f.3g.4i.5i., 1f.2f.3g.4i.5i., 1h.2f.3g.4i.5i., 1j.2f.3g.4i.5i.,1p.2f.3g.4i.5i., 1a.2i.3g.4i.5i., 1b.2i.3g.4i.5i., 1f.2i.3g.4i.5i.,1h.2i.3g.4i.5i., 1j.2i.3g.4i.5i., 1p.2i.3g.4i.5i., 1a.2m.3g.4i.5i.,1b.2m.3g.4i.5i., 1f.2m.3g.4i.5i., 1h.2m.3g.4i.5i., 1j.2m.3g.4i.5i.,1p.2m.3g.4i.5i., 1a.2o.3g.4i.5i., 1b.2o.3g.4i.5i., 1f.2o.3g.4i.5i.,1h.2o.3g.4i.5i., 1j.2o.3g.4i.5i., 1p.2o.3g.4i.5i., 1a.2u.3g.4i.5i.,1b.2u.3g.4i.5i., 1f.2u.3g.4i.5i., 1h.2u.3g.4i.5i., 1j.2u.3g.4i.5i.,1p.2u.3g.4i.5i., 1a.2y.3g.4i.5i., 1b.2y.3g.4i.5i., 1f.2y.3g.4i.5i.,1h.2y.3g.4i.5i., 1j.2y.3g.4i.5i., and 1p.2y.3g.4i.5i..

In still yet another embodiment, the compound of the present inventionhas an inhibition activity against P450 at a level equal to or betterthan the inhibition activity of a compound as represented by an IC₅₀ ofless than about 2000 nM, less than about 1500 nM, less than about 1000nM, less than about 900 nM, less than about 800 nM, less than about 700nM, less than about 650 nM, less than about 600 nM, less than about 550nM, less than about 500 nM, less than about 400 nM, less than about 350nM, less than about 300 nM, less than about 250 nM, less than about 200nM, less than about 100 nM, or less than about 50 nM.

In still yet another embodiment, the compound of the present inventionhas an inhibition activity against an isozyme of P450, e.g., 3A in arange represented by IC₅₀ from about 2000 nM to about 100 nM, from about1000 nM to about 100 nM, from about 900 nM to about 200 nM, from about800 nM to about 300 nM, from about 700 nM to about 200 nM, from about600 nM to about 200 nM, from about 500 nM to about 200 nM, from about700 nM to about 300 nM, from about 600 nM to about 300 nM, from about700 nM to about 400 nM, from about 600 nM to about 400 nM, from about400 nM to about 100 nM, from about 300 nM to about 100 nM, or from about600 nM to about 150 nM.

In still yet another embodiment, the compound of the present inventionhas an inhibition activity against P450 at a level equal to or betterthan the inhibition activity of a compound as represented by an IC₅₀ ofless than about 2000 nM, less than about 1500 nM, less than about 1000nM, less than about 900 nM, less than about 800 nM, less than about 700nM, less than about 650 nM, less than about 600 nM, less than about 550nM, less than about 500 nM, less than about 400 nM, less than about 350nM, less than about 300 nM, less than about 250 nM, less than about 200nM, less than about 100 nM, or less than about 50 nM, provided that suchcompound also does not substantially exhibit biological activities otherthan its inhibition activity against P450. For example, the compound ofthe present invention can have a reduced or not significant activity ofprotease inhibition, including without any limitation a level ofprotease inhibition as represented by HIV EC₅₀ of greater than about1000 nM, greater than about 900 nM, greater than about 800 nM, greaterthan about 700 nM, greater than about 600 nM, greater than about 500 nM,greater than about 400 nM, greater than about 300 nM, greater than about200 nM, greater than about 100 nM, greater than about 50 nM, greaterthan about 40 nM, greater than about 30 nM, greater than about 20 nM,greater than about 10 nM, greater than about 5 nM, or greater than about1 nM.

In yet another embodiment, the compound of the present invention has aninhibition activity specifically against one or more isozymes of P450including without limitation 1A2, 2B6, 2C8, 2C19, 2C9, 2D6, 2E1, and3A4, 5, 7, etc.

In yet another embodiment, the compound of the present invention has aninhibition activity specifically against an isozyme of P450 that isinvolved in metabolizing anti-viral drugs, e.g., indinavir, nelfinavir,ritonavir, saquinavir etc.

In still yet another embodiment, the compound of the present inventionhas an inhibition activity specifically against one or more isozymes ofP450, but not the other(s). For example, the compound of the presentinvention can have an inhibition activity specifically against P450 3A,but a reduced, insubstantial, or minimum inhibition activity againstanother isozyme of P450, e.g., P450 2C9.

Pharmaceutical Formulations

The compounds of this invention are formulated with conventionalcarriers and excipients, which will be selected in accord with ordinarypractice. Tablets will contain excipients, glidants, fillers, bindersand the like. Aqueous formulations are prepared in sterile form, andwhen intended for delivery by other than oral administration generallywill be isotonic. All formulations will optionally contain excipientssuch as those set forth in the Handbook of Pharmaceutical Excipients(1986), herein incorporated by reference in its entirety. Excipientsinclude ascorbic acid and other antioxidants, chelating agents such asEDTA, carbohydrates such as dextrin, hydroxyalkylcellulose,hydroxyalkylmethylcellulose, stearic acid and the like. The pH of theformulations ranges from about 3 to about 11, but is ordinarily about 7to 10.

While it is possible for the active ingredients to be administered aloneit may be preferable to present them as pharmaceutical formulations. Theformulations of the invention, both for veterinary and for human use,comprise at least one active ingredient, e.g. a compound of the presentinvention, together with one or more acceptable carriers and optionallyother therapeutic ingredients. The carrier(s) must be “acceptable” inthe sense of being compatible with the other ingredients of theformulation and physiologically innocuous to the recipient thereof.

The formulations include those suitable for the foregoing administrationroutes. The formulations may conveniently be presented in unit dosageform and may be prepared by any of the methods well known in the art ofpharmacy. Techniques and formulations generally are found in Remington'sPharmaceutical Sciences (Mack Publishing Co., Easton, Pa.), hereinincorporated by reference in its entirety. Such methods include the stepof bringing into association the active ingredient with the carrierwhich constitutes one or more accessory ingredients. In general theformulations are prepared by uniformly and intimately bringing intoassociation the active ingredient with liquid carriers or finely dividedsolid carriers or both, and then, if necessary, shaping the product.

Formulations of the present invention suitable for oral administrationmay be presented as discrete units such as capsules, cachets or tabletseach containing a predetermined amount of the active ingredient; as apowder or granules; as a solution or a suspension in an aqueous ornon-aqueous liquid; or as an oil-in-water liquid emulsion or awater-in-oil liquid emulsion. The active ingredient may also beadministered as a bolus, electuary or paste.

A tablet is made by compression or molding, optionally with one or moreaccessory ingredients. Compressed tablets may be prepared by compressingin a suitable machine the active ingredient in a free-flowing form suchas a powder or granules, optionally mixed with a binder, lubricant,inert diluent, preservative, surface active or dispersing agent. Moldedtablets may be made by molding in a suitable machine a mixture of thepowdered active ingredient moistened with an inert liquid diluent. Thetablets may optionally be coated or scored and optionally are formulatedso as to provide slow or controlled release of the active ingredient.

For administration to the eye or other external tissues e.g., mouth andskin, the formulations are preferably applied as a topical ointment orcream containing the active ingredient(s) in an amount of, for example,0.075 to 20% w/w (including active ingredient(s) in a range between 0.1%and 20% in increments of 0.1% w/w such as 0.6% w/w, 0.7% w/w, etc.),preferably 0.2 to 15% w/w and most preferably 0.5 to 10% w/w. Whenformulated in an ointment, the active ingredients may be employed witheither a paraffinic or a water-miscible ointment base. Alternatively,the active ingredients may be formulated in a cream with an oil-in-watercream base.

If desired, the aqueous phase of the cream base may include, forexample, at least 30% w/w of a polyhydric alcohol, i.e. an alcoholhaving two or more hydroxyl groups such as propylene glycol, butane1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol(including PEG 400) and mixtures thereof. The topical formulations maydesirably include a compound which enhances absorption or penetration ofthe active ingredient through the skin or other affected areas. Examplesof such dermal penetration enhancers include dimethyl sulphoxide andrelated analogs.

The oily phase of the emulsions of this invention may be constitutedfrom known ingredients in a known manner. While the phase may comprisemerely an emulsifier (otherwise known as an emulgent), it desirablycomprises a mixture of at least one emulsifier with a fat or an oil orwith both a fat and an oil. Preferably, a hydrophilic emulsifier isincluded together with a lipophilic emulsifier which acts as astabilizer. It is also preferred to include both an oil and a fat.Together, the emulsifier(s) with or without stabilizer(s) make up theso-called emulsifying wax, and the wax together with the oil and fatmake up the so-called emulsifying ointment base which forms the oilydispersed phase of the cream formulations.

Emulgents and emulsion stabilizers suitable for use in the formulationof the invention include Tween® 60, Span® 80, cetostearyl alcohol,benzyl alcohol, myristyl alcohol, glyceryl mono-stearate and sodiumlauryl sulfate.

The choice of suitable oils or fats for the formulation is based onachieving the desired cosmetic properties. The cream should preferablybe a non-greasy, non-staining and washable product with suitableconsistency to avoid leakage from tubes or other containers. Straight orbranched chain, mono- or dibasic alkyl esters such as di-isoadipate,isocetyl stearate, propylene glycol diester of coconut fatty acids,isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate,2-ethylhexyl palmitate or a blend of branched chain esters known asCrodamol CAP may be used, the last three being preferred esters. Thesemay be used alone or in combination depending on the propertiesrequired. Alternatively, high melting point lipids such as white softparaffin and/or liquid paraffin or other mineral oils are used.

Pharmaceutical formulations according to the present invention compriseone or more compounds of the invention together with one or morepharmaceutically acceptable carriers or excipients and optionally othertherapeutic agents. Pharmaceutical formulations containing the activeingredient may be in any form suitable for the intended method ofadministration. When used for oral use for example, tablets, troches,lozenges, aqueous or oil suspensions, dispersible powders or granules,emulsions, hard or soft capsules, syrups or elixirs may be prepared.Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsincluding sweetening agents, flavoring agents, coloring agents andpreserving agents, in order to provide a palatable preparation. Tabletscontaining the active ingredient in admixture with non-toxicpharmaceutically acceptable excipient which are suitable for manufactureof tablets are acceptable. These excipients may be, for example, inertdiluents, such as calcium or sodium carbonate, lactose, lactosemonohydrate, croscarmellose sodium, povidone, calcium or sodiumphosphate; granulating and disintegrating agents, such as maize starch,or alginic acid; binding agents, such as cellulose, microcrystallinecellulose, starch, gelatin or acacia; and lubricating agents, such asmagnesium stearate, stearic acid or talc. Tablets may be uncoated or maybe coated by known techniques including microencapsulation to delaydisintegration and adsorption in the gastrointestinal tract and therebyprovide a sustained action over a longer period. For example, a timedelay material such as glyceryl monostearate or glyceryl distearatealone or with a wax may be employed.

Formulations for oral use may be also presented as hard gelatin capsuleswhere the active ingredient is mixed with an inert solid diluent, forexample calcium phosphate or kaolin, or as soft gelatin capsules whereinthe active ingredient is mixed with water or an oil medium, such aspeanut oil, liquid paraffin or olive oil.

Aqueous suspensions of the invention contain the active materials inadmixture with excipients suitable for the manufacture of aqueoussuspensions. Such excipients include a suspending agent, such as sodiumcarboxymethylcellulose, methylcellulose, hydroxypropyl methylcelluose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia,and dispersing or wetting agents such as a naturally occurringphosphatide (e.g., lecithin), a condensation product of an alkyleneoxide with a fatty acid (e.g., polyoxyethylene stearate), a condensationproduct of ethylene oxide with a long chain aliphatic alcohol (e.g.,heptadecaethyleneoxycetanol), a condensation product of ethylene oxidewith a partial ester derived from a fatty acid and a hexitol anhydride(e.g., polyoxyethylene sorbitan monooleate). The aqueous suspension mayalso contain one or more preservatives such as ethyl or n-propylp-hydroxy-benzoate, one or more coloring agents, one or more flavoringagents and one or more sweetening agents, such as sucrose or saccharin.

Oil suspensions may be formulated by suspending the active ingredient ina vegetable oil, such as arachis oil, olive oil, sesame oil or coconutoil, or in a mineral oil such as liquid paraffin. The oral suspensionsmay contain a thickening agent, such as beeswax, hard paraffin or cetylalcohol. Sweetening agents, such as those set forth herein, andflavoring agents may be added to provide a palatable oral preparation.These compositions may be preserved by the addition of an antioxidantsuch as ascorbic acid.

Dispersible powders and granules of the invention suitable forpreparation of an aqueous suspension by the addition of water providethe active ingredient in admixture with a dispersing or wetting agent, asuspending agent, and one or more preservatives. Suitable dispersing orwetting agents and suspending agents are exemplified by those disclosedabove. Additional excipients, for example sweetening, flavoring andcoloring agents, may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, suchas olive oil or arachis oil, a mineral oil, such as liquid paraffin, ora mixture of these. Suitable emulsifying agents includenaturally-occurring gums, such as gum acacia and gum tragacanth,naturally occurring phosphatides, such as soybean lecithin, esters orpartial esters derived from fatty acids and hexitol anhydrides, such assorbitan monooleate, and condensation products of these partial esterswith ethylene oxide, such as polyoxyethylene sorbitan monooleate. Theemulsion may also contain sweetening and flavoring agents. Syrups andelixirs may be formulated with sweetening agents, such as glycerol,sorbitol or sucrose. Such formulations may also contain a demulcent, apreservative, a flavoring or a coloring agent.

The pharmaceutical compositions of the invention may be in the form of asterile injectable preparation, such as a sterile injectable aqueous oroleaginous suspension. This suspension may be formulated according tothe known art using those suitable dispersing or wetting agents andsuspending agents which have been mentioned herein. The sterileinjectable preparation may also be a sterile injectable solution orsuspension in a non-toxic parenterally acceptable diluent or solvent,such as a solution in 1,3-butane-diol or prepared as a lyophilizedpowder. Among the acceptable vehicles and solvents that may be employedare water, Ringer's solution and isotonic sodium chloride solution. Inaddition, sterile fixed oils may conventionally be employed as a solventor suspending medium. For this purpose any bland fixed oil may beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid may likewise be used in the preparation ofinjectables.

The amount of active ingredient that may be combined with the carriermaterial to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. For example, atime-release formulation intended for oral administration to humans maycontain approximately 1 to 1000 mg of active material compounded with anappropriate and convenient amount of carrier material which may varyfrom about 5 to about 95% of the total compositions (weight:weight). Thepharmaceutical composition can be prepared to provide easily measurableamounts for administration. For example, an aqueous solution intendedfor intravenous infusion may contain from about 3 to 500 μg of theactive ingredient per milliliter of solution in order that infusion of asuitable volume at a rate of about 30 mL/hr can occur.

Formulations suitable for administration to the eye include eye dropswherein the active ingredient is dissolved or suspended in a suitablecarrier, especially an aqueous solvent for the active ingredient. Theactive ingredient is preferably present in such formulations in aconcentration of 0.5 to 20%, advantageously 0.5 to 10% particularlyabout 1.5% w/w.

Formulations suitable for topical administration in the mouth includelozenges comprising the active ingredient in a flavored basis, usuallysucrose and acacia or tragacanth; pastilles comprising the activeingredient in an inert basis such as gelatin and glycerin, or sucroseand acacia; and mouthwashes comprising the active ingredient in asuitable liquid carrier.

Formulations for rectal administration may be presented as a suppositorywith a suitable base comprising for example cocoa butter or asalicylate.

Formulations suitable for intrapulmonary or nasal administration have aparticle size for example in the range of 0.1 to 500 μm (includingparticle sizes in a range between 0.1 and 500 μm in increments such as0.5 μm, 1 μm, 30 μm, 35 μm, etc.), which is administered by rapidinhalation through the nasal passage or by inhalation through the mouthso as to reach the alveolar sacs. Suitable formulations include aqueousor oily solutions of the active ingredient. Formulations suitable foraerosol or dry powder administration may be prepared according toconventional methods and may be delivered with other therapeutic agentssuch as compounds heretofore used in the treatment or prophylaxis ofinfections as described herein.

Formulations suitable for vaginal administration may be presented aspessaries, tampons, creams, gels, pastes, foams or spray formulationscontaining in addition to the active ingredient such carriers as areknown in the art to be appropriate.

Formulations suitable for parenteral administration include aqueous andnon-aqueous sterile injection solutions which may contain anti-oxidants,buffers, bacteriostats and solutes which render the formulation isotonicwith the blood of the intended recipient; and aqueous and non-aqueoussterile suspensions which may include suspending agents and thickeningagents.

The formulations are presented in unit-dose or multi-dose containers,for example sealed ampoules and vials, and may be stored in afreeze-dried (lyophilized) condition requiring only the addition of thesterile liquid carrier, for example water for injection, immediatelyprior to use. Extemporaneous injection solutions and suspensions areprepared from sterile powders, granules and tablets of the kindpreviously described. Preferred unit dosage formulations are thosecontaining a daily dose or unit daily sub-dose, as herein above recited,or an appropriate fraction thereof, of the active ingredient.

It should be understood that in addition to the ingredients provided bythe present invention the formulations of this invention may includeother agents conventional in the art having regard to the type offormulation in question, for example those suitable for oraladministration may include flavoring agents.

The invention further provides veterinary compositions comprising atleast one active ingredient, e.g., a compound of the present inventiontogether with a veterinary carrier.

Veterinary carriers are materials useful for the purpose ofadministering the composition and may be solid, liquid or gaseousmaterials which are otherwise inert or acceptable in the veterinary artand are compatible with the active ingredient. These veterinarycompositions may be administered orally, parenterally or by any otherdesired route.

Compounds of the invention can also be formulated to provide controlledrelease of the active ingredient to allow less frequent dosing or toimprove the pharmacokinetic or toxicity profile of the activeingredient. Accordingly, the invention also provided compositionscomprising one or more compounds of the invention formulated forsustained or controlled release.

The effective dose of an active ingredient depends at least on thenature of the condition being treated, toxicity, whether the compound isbeing used prophylactically (lower doses) or against an active diseaseor condition, the method of delivery, and the pharmaceuticalformulation, and will be determined by the clinician using conventionaldose escalation studies. The effective dose can be expected to be fromabout 0.0001 to about 100 mg/kg body weight per day. Typically, fromabout 0.01 to about 10 mg/kg body weight per day. More typically, fromabout 0.01 to about 5 mg/kg body weight per day. More typically, fromabout 0.05 to about 0.5 mg/kg body weight per day. For example, thedaily candidate dose for an adult human of approximately 70 kg bodyweight will range from 1 mg to 1000 mg, or between 5 mg and 500 mg, andmay take the form of single or multiple doses.

In yet another embodiment, the present application disclosespharmaceutical compositions comprising a compound of the presentinvention, or a pharmaceutically acceptable salt, solvate, and/or esterthereof, and a pharmaceutically acceptable carrier or excipient.

In yet another embodiment, the present application disclosespharmaceutical compositions comprising a compound of the presentinvention, or a pharmaceutically acceptable salt, solvate, and/or esterthereof, in combination with at least one additional therapeutic agent,and a pharmaceutically acceptable carrier or excipient.

According to the present invention, the therapeutic agent used incombination with the compound of the present invention can be any agenthaving a therapeutic effect when used in combination with the compoundof the present invention. For example, the therapeutic agent used incombination with the compound of the present invention can be any agentthat is accessible to oxidative metabolism by cytochrome P450 enzymes,especially cytochrome P450 monooxygenase, e.g., 1A2, 2B6, 2C8, 2C19,2C9, 2D6, 2E1, 3A4,5,7, etc.

In another example, the therapeutic agent used in combination with thecompound of the present invention can be any anti-viral agent, e.g.,anti-HIV, anti-HCV, etc., anti-bacterial agent, anti-fungal agent,immuno-modulator, e.g., immunosuppressant, anti-neoplastic agent,chemotherapeutic agent, agents useful for treating cardiovascularconditions, neurological conditions, etc.

In yet another example, the therapeutic agent used in combination withthe compound of the present invention can be any proton pump inhibitor,anti-epileptics, NSAID, oral hypoglycemic agent, angiotensin II,sulfonylureas, beta blocker, antidepressant, antipsychotics, oranesthetics, or a combination thereof.

In yet another example, the therapeutic agent used in combination withthe compound of the present invention can be any 1) macrolideantibiotics, e.g., clarithromycin, erythromycin, telithromycin, 2)anti-arrhythmics, e.g., quinidine=>3-OH, 3) benzodiazepines, e.g.,alprazolam, diazepam=>3OH, midazolam, triazolam, 4) immune modulators,e.g., cyclosporine, tacrolimus (FK506), 5) HIV antivirals, e.g.,indinavir, nelfinavir, ritonavir, saquinavir, 6) prokinetic, e.g.,cisapride, 7) antihistamines, e.g., astemizole, chlorpheniramine,terfenidine, 8) calcium channel blockers, e.g., amlodipine, diltiazem,felodipine, lercanidipine, nifedipine, nisoldipine, nitrendipine,verapamil, 9) HMG CoA reductase inhibitors, e.g., atorvastatin,cerivastatin, lovastatin, simvastatin, or 10) steroid 6beta-OH, e.g.,estradiol, hydrocortisone, progesterone, testosterone.

In still yet another example, the therapeutic agent used in combinationwith the compound of the present invention can be any alfentanyl,aprepitant, aripiprazole, buspirone, cafergot, caffeine, TMU, cilostazolcocaine, codeine-N-demethylation, dapsone, dextromethorphan, docetaxel,domperidone, eplerenone, fentanyl, finasteride, gleevec, haloperidol,irinotecan, LAAM, lidocaine, methadone, nateglinide, ondansetron,pimozide, propranolol, quetiapine, quinine, salmeterol, sildenafil,sirolimus, tamoxifen, taxol, terfenadine, trazodone, vincristine,zaleplon, or zolpidem or a combination thereof.

In one embodiment, the present application discloses pharmaceuticalcompositions comprising a compound of the present invention, or apharmaceutically acceptable salt, solvate, and/or ester thereof, incombination with at least one additional therapeutic agent selected fromthe group consisting of HIV protease inhibiting compounds, HIVnon-nucleoside inhibitors of reverse transcriptase, HIV nucleosideinhibitors of reverse transcriptase, HIV nucleotide inhibitors ofreverse transcriptase, HIV integrase inhibitors, non-nucleosideinhibitors of HCV, CCR5 inhibitors, and combinations thereof, and apharmaceutically acceptable carrier or excipient.

In another embodiment, the present application provides pharmaceuticalcompositions comprising a compound of the present invention, or apharmaceutically acceptable salt, solvate, and/or ester thereof, incombination with at least one additional therapeutic agent selected fromthe group consisting of amprenavir, atazanavir, fosamprenavir,indinavir, lopinavir, ritonavir, nelfinavir, saquinavir, tipranavir,brecanavir, darunavir, TMC-126, TMC-114, mozenavir (DMP-450), JE-2147(AG1776), L-756423, RO0334649, KNI-272, DPC-681, DPC-684, GW640385X,capravirine, emivirine, delaviridine, efavirenz, nevirapine, (+)calanolide A, etravirine, GW5634, DPC-083, DPC-961, DPC-963, MIV-150,TMC-120, zidovudine, emtricitabine, didanosine, stavudine, zalcitabine,lamivudine, abacavir, amdoxovir, elvucitabine, alovudine, MIV-210,Racivir (±-FTC), D-d4FC, AVX754, tenofovir disoproxil fumarate,adefovir, curcumin, derivatives of curcumin, chicoric acid, derivativesof chicoric acid, 3,5-dicaffeoylquinic acid, derivatives of3,5-dicaffeoylquinic acid, aurintricarboxylic acid, derivatives ofaurintricarboxylic acid, caffeic acid phenethyl ester, derivatives ofcaffeic acid phenethyl ester, tyrphostin, derivatives of tyrphostin,quercetin, derivatives of quercetin, S-1360, zintevir (AR-177),L-870812, L-870810, benzimidazole derivatives, benzo-1,2,4-thiadiazinederivatives, phenylalanine derivatives, aplaviroc, vicriviroc, andmaraviroc, cyclosporine, FK-506, rapamycin, taxol, taxotere,clarithromycin, A-77003, A-80987, MK-639, saquinavir, VX-478, AG1343,DMP-323, XM-450, BILA 2011 BS, BILA 1096 BS, BILA 2185 BS, BMS 186,318,LB71262, SC-52151, SC-629(N,N-dimethylglycyl-N-(2-hydroxy-3-(((4-methoxyphenyl)sulphonyl)(2-methylpropyl)amino)-1-(phenylmethyl)propyl)-3-methyl-L-valinamide),KNI-272, CGP 53437, CGP 57813 and U-103017 and a pharmaceuticallyacceptable carrier or excipient.

In yet another embodiment, the present application provides acombination pharmaceutical agent comprising:

a) a first pharmaceutical composition comprising a compound of thepresent invention, or a pharmaceutically acceptable salt, solvate, orester thereof; and

b) a second pharmaceutical composition comprising at least oneadditional therapeutic agent selected from the group consisting of HIVprotease inhibiting compounds, HIV non-nucleoside inhibitors of reversetranscriptase, HIV nucleoside inhibitors of reverse transcriptase, HIVnucleotide inhibitors of reverse transcriptase, HIV integraseinhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5inhibitors, interferons, ribavirin analogs, NS3 protease inhibitors,alpha-glucosidase 1 inhibitors, hepatoprotectants, non-nucleosideinhibitors of HCV, and other drugs for treating HCV, and combinationsthereof.

Routes of Administration

One or more compounds of the invention (herein referred to as the activeingredients) are administered by any route appropriate to the conditionto be treated. Suitable routes include oral, rectal, nasal, topical(including buccal and sublingual), vaginal and parenteral (includingsubcutaneous, intramuscular, intravenous, intradermal, intrathecal andepidural), and the like. It will be appreciated that the preferred routemay vary with for example the condition of the recipient. An advantageof the compounds of this invention is that they are orally bioavailableand can be dosed orally.

Combination Therapy

In one embodiment, the compounds of the present invention can be usedalone, e.g., for inhibiting cytochrome P450 monooxygenase. In anotherembodiment, the compounds of the present invention are used incombination with other active therapeutic ingredients or agents.Preferably, the other active therapeutic ingredients or agents aremetabolized or accessible to the oxidative metabolism by cytochrome P450enzymes, e.g., monooxygenase enzymes such as 1A2, 2B6, 2C8, 2C19, 2C9,2D6, 2E1, 3A4,5,7, etc.

Combinations of the compounds of the present invention are typicallyselected based on the condition to be treated, cross-reactivities ofingredients and pharmaco-properties of the combination. For example,when treating an infection (e.g., HIV or HCV), the compositions of theinvention are combined with anti-infective agents (such as thosedescribed herein).

In one embodiment, non-limiting examples of suitable combinationsinclude combinations of one or more compounds of the present inventionwith one or more anti-viral agents, e.g., anti-HIV, anti-HCV, etc.,anti-bacterial agents, anti-fungal agents, immuno-modulators, e.g.,immunosuppressant, anti-neoplastic agents, chemotherapeutic agents,agents useful for treating cardiovascular conditions, neurologicalconditions, etc.

In another embodiment, non-limiting examples of suitable combinationsinclude combinations of one or more compounds of the present inventionwith one or more proton pump inhibitors, anti-epileptics, NSAIDs, oralhypoglycemic agents, angiotensin II, sulfonylureas, beta blockers,antidepressants, antipsychotics, or anesthetics, or a combinationthereof.

In yet another embodiment, non-limiting examples of suitablecombinations include combinations of one or more compounds of thepresent invention with one or more 1) macrolide antibiotics, e.g.,clarithromycin, erythromycin, telithromycin, 2) anti-arrhythmics, e.g.,quinidine=>3-OH, 3) benzodiazepines, e.g., alprazolam, diazepam=>3OH,midazolam, triazolam, 4) immune modulators, e.g., cyclosporine,tacrolimus (FK506), 5) HIV antivirals, e.g., indinavir, nelfinavir,ritonavir, saquinavir, 6) prokinetic, e.g., cisapride, 7)antihistamines, e.g., astemizole, chlorpheniramine, terfenidine, 8)calcium channel blockers, e.g., amlodipine, diltiazem, felodipine,lercanidipine, nifedipine, nisoldipine, nitrendipine, verapamil, 9) HMGCoA reductase inhibitors, e.g., atorvastatin, cerivastatin, lovastatin,simvastatin, or 10) steroid 6beta-OH, e.g., estradiol, hydrocortisone,progesterone, testosterone.

In still yet another embodiment, non-limiting examples of suitablecombinations include combinations of one or more compounds of thepresent invention with one or more compounds selected from the groupconsisting of alfentanyl, aprepitant, aripiprazole, buspirone, cafergot,caffeine=>TMU, cilostazol, cocaine, codeine-N-demethylation, dapsone,dextromethorphan, docetaxel, domperidone, eplerenone, fentanyl,finasteride, gleevec, haloperidol, irinotecan, LAAM, lidocaine,methadone, nateglinide, odanestron, pimozide, propranolol, quetiapine,quinine, salmeterol, sildenafil, sirolimus, tamoxifen, taxol,terfenadine, trazodone, vincristine, zaleplon, and zolpidem or acombination thereof.

In still yet another embodiment, non-limiting examples of suitablecombinations include combinations of one or more compounds of thepresent invention with one or more HIV protease inhibiting compounds,HIV non-nucleoside inhibitors of reverse transcriptase, HIV nucleosideinhibitors of reverse transcriptase, HIV nucleotide inhibitors ofreverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4inhibitors, gp120 inhibitors, CCR5 inhibitors, and other drugs fortreating HIV, interferons, ribavirin analogs, HCV NS3 proteaseinhibitors, alpha-glucosidase 1 inhibitors, hepatoprotectants,nucleoside or nucleotide inhibitors of HCV, non-nucleoside inhibitors ofHCV, and other drugs for treating HCV.

More specifically, one or more compounds of the present invention may becombined with one or more compounds selected from the group consistingof 1) amprenavir, atazanavir, fosamprenavir, indinavir, lopinavir,ritonavir, nelfinavir, saquinavir, tipranavir, brecanavir, darunavir,TMC-126, TMC-114, mozenavir (DMP-450), JE-2147 (AG1776), L-756423,RO0334649, KNI-272, DPC-681, DPC-684, GW640385X, DG17, GS-8374, PPL-100,DG35, and AG 1859, 2) a HIV non-nucleoside inhibitor of reversetranscriptase, e.g., capravirine, emivirine, delaviridine, efavirenz,nevirapine, (+) calanolide A, etravirine, GW5634, DPC-083, DPC-961,DPC-963, MIV-150, and TMC-120, TMC-278 (rilpivirene), efavirenz, BILR355 BS, VRX 840773, UK-453061, and RDEA806, 3) a HIV nucleosideinhibitor of reverse transcriptase, e.g., zidovudine, emtricitabine,didanosine, stavudine, zalcitabine, lamivudine, abacavir, amdoxovir,elvucitabine, alovudine, MIV-210, racivir (±-FTC), D-d4FC,emtricitabine, phosphazide, fozivudine tidoxil, apricitibine (AVX754),GS-7340, KP-1461, and fosalvudine tidoxil (formerly HDP 99.0003), 4) aHIV nucleotide inhibitor of reverse transcriptase, e.g., tenofovir andadefovir, 5) a HIV integrase inhibitor; e.g., curcumin, derivatives ofcurcumin, chicoric acid, derivatives of chicoric acid,3,5-dicaffeoylquinic acid, derivatives of 3,5-dicaffeoylquinic acid,aurintricarboxylic acid, derivatives of aurintricarboxylic acid, caffeicacid phenethyl ester, derivatives of caffeic acid phenethyl ester,tyrphostin, derivatives of tyrphostin, quercetin, derivatives ofquercetin, S-1360, zintevir (AR-177), elvitegravir, L-870812, andL-870810, MK-0518 (raltegravir), BMS-538158, GSK364735C, BMS-707035,MK-2048, and BA 011, 6) a gp41 inhibitor, e.g., enfuvirtide,sifuvirtide, FB006M, and TRI-1144, 7) a CXCR4 inhibitor, e.g., AMD-070,8) an entry inhibitor, e.g., SP01A, 9) a gp120 inhibitor, e.g.,BMS-488043 or BlockAide/CR, 10) a G6PD and NADH-oxidase inhibitor, e.g.,immunitin, 11) a CCR5 inhibitor, e.g., aplaviroc, vicriviroc, maraviroc,PRO-140, INCB15050, PF-232798 (Pfizer), and CCR5 mAb004, 12) other drugsfor treating HIV, e.g., BAS-100, SPI-452, REP 9, SP-01A, TNX-355, DES6,ODN-93, ODN-112, VGV-1, PA-457 (bevirimat), Ampligen, HRG214, Cytolin,VGX-410, KD-247, AMZ 0026, CYT 99007A-221 HIV, DEBIO-025, BAY 50-4798,MDX010 (ipilimumab), PBS119, ALG 889, and PA-1050040 (PA-040), 13) aninterferon, e.g., pegylated rIFN-alpha 2b, pegylated rIFN-alpha 2a,rIFN-alpha 2b, rIFN-alpha 2a, consensus IFN alpha (infergen), feron,reaferon, intermax alpha, r-IFN-beta, infergen+actimmune, IFN-omega withDUROS, albuferon, locteron, Albuferon, Rebif, Oral interferon alpha,IFNalpha-2b XL, AVI-005, PEG-Infergen, and Pegylated IFN-beta, 14) aribavirin analog, e.g., rebetol, copegus, viramidine (taribavirin), 15)a NS5b polymerase inhibitor, e.g., NM-283, valopicitabine, R1626,PSI-6130 (R1656), HCV-796, BILB 1941, XTL-2125, MK-0608, NM-107, R7128(R4048), VCH-759, PF-868554, and GSK625433, 16) A NS3 proteaseinhibitor, e.g., SCH-503034 (SCH-7), VX-950 (telaprevir), BILN-2065,BMS-605339, and ITMN-191, 17) an alpha-glucosidase 1 inhibitor, e.g.,MX-3253 (celgosivir), UT-231B, 18) hepatoprotectants, e.g., IDN-6556, ME3738, LB-84451, and MitoQ, 19) a non-nucleoside inhibitor of HCV, e.g.,benzimidazole derivatives, benzo-1,2,4-thiadiazine derivatives,phenylalanine derivatives, A-831, GS-9190, and A-689; and 20) otherdrugs for treating HCV, e.g., zadaxin, nitazoxanide (alinea), BIVN-401(virostat), PYN-17 (altirex), KPE02003002, actilon (CPG-10101),KRN-7000, civacir, GI-5005, ANA-975, XTL-6865, ANA 971, NOV-205,tarvacin, EHC-18, NIM811, DEBIO-025, VGX-410C, EMZ-702, AVI 4065,Bavituximab, Oglufanide, and VX-497 (merimepodib).

It is also contemplated that the compounds of the present invention canbe used with any other active therapeutic agent or ingredient which isappreciably metabolized by cytochrome P450 monooxygenase enzymes, e.g.cytochrome P450 monooxygenase 3A, thereby reducing the amount or rate atwhich the other active therapeutic agent or ingredient is metabolized,whereby the pharmacokinetics of the other active therapeutic agent oringredient is improved. Such improvements can include elevating theblood plasma levels of the other therapeutic agent or ingredient ormaintaining a more therapeutically effective blood plasma level of theother therapeutic active agent or ingredient—compared to blood plasmalevels of the other therapeutic agent or ingredient administered withoutthe compound of the present invention.

It is also possible to combine any compound of the invention with one ormore other active therapeutic agents in a unitary dosage form forsimultaneous or sequential administration to a patient. The combinationtherapy may be administered as a simultaneous or sequential regimen.When administered sequentially, the combination may be administered intwo or more administrations.

Co-administration of a compound of the invention with one or more otheractive therapeutic agents generally refers to simultaneous or sequentialadministration of a compound of the invention and one or more otheractive therapeutic agents, such that therapeutically effective amountsof the compound of the invention and one or more other activetherapeutic agents are both present in the body of the patient.

Co-administration includes administration of unit dosages of thecompounds of the invention before or after administration of unitdosages of one or more other active therapeutic agents, for example,administration of the compounds of the invention within seconds,minutes, or hours of the administration of one or more other activetherapeutic agents. For example, a unit dose of a compound of theinvention can be administered first, followed within seconds or minutesby administration of a unit dose of one or more other active therapeuticagents. Alternatively, a unit dose of one or more other therapeuticagents can be administered first, followed by administration of a unitdose of a compound of the invention within seconds or minutes. In somecases, it may be desirable to administer a unit dose of a compound ofthe invention first, followed, after a period of hours (e.g., 1-12hours), by administration of a unit dose of one or more other activetherapeutic agents. In other cases, it may be desirable to administer aunit dose of one or more other active therapeutic agents first,followed, after a period of hours (e.g., 1-12 hours), by administrationof a unit dose of a compound of the invention.

The combination therapy may provide “synergy” and “synergistic effect”,i.e. the effect achieved when the active ingredients used together isgreater than the sum of the effects that results from using thecompounds separately. A synergistic effect may be attained when theactive ingredients are: (1) co-formulated and administered or deliveredsimultaneously in a combined formulation; (2) delivered by alternationor in parallel as separate formulations; or (3) by some other regimen.When delivered in alternation therapy, a synergistic effect may beattained when the compounds are administered or delivered sequentially,e.g., in separate tablets, pills or capsules, or by different injectionsin separate syringes. In general, during alternation therapy, aneffective dosage of each active ingredient is administered sequentially,i.e. serially, whereas in combination therapy, effective dosages of twoor more active ingredients are administered together.

In yet another embodiment, the present application provides a method forimproving the pharmacokinetics of a drug which is metabolized bycytochrome P450 monooxygenase, comprising administering to a patienttreated with said drug, a therapeutically effective amount of a compoundof The present invention, or a pharmaceutically acceptable salt,solvate, and/or ester thereof.

In yet another embodiment, the present application provides a method forimproving the pharmacokinetics of a drug which is metabolized bycytochrome P450 monooxygenase, comprising administering to a patienttreated with said drug, a therapeutically effective amount of acombination comprising said drug and a compound of the presentinvention, or a pharmaceutically acceptable salt, solvate, and/or esterthereof.

In yet another embodiment, the present application provides a method forimproving the pharmacokinetics of a drug which is metabolized bycytochrome P450 monooxygenase 3A, comprising administering to a patienttreated with said drug, a therapeutically effective amount of a compoundof the present invention, or a pharmaceutically acceptable salt,solvate, and/or ester thereof.

In yet another embodiment, the present application provides a method forincreasing blood plasma levels of a drug which is metabolized bycytochrome P450 monooxygenase, comprising administering to a patienttreated with said drug, a therapeutically effective amount of a compoundof the present invention, or a pharmaceutically acceptable salt,solvate, and/or ester thereof.

In yet another embodiment, the present application provides a method forincreasing blood plasma levels of a drug which is metabolized bycytochrome P450 monooxygenase, comprising administering to a patienttreated with said drug, a therapeutically effective amount of acombination comprising said drug and a compound of the presentinvention, or a pharmaceutically acceptable salt, solvate, and/or esterthereof.

In yet another embodiment, the present application provides a method forincreasing blood plasma levels of a drug which is metabolized bycytochrome P450 monooxygenase 3A, comprising administering to a patienttreated with said drug, a therapeutically effective amount of a compoundof the present invention, or a pharmaceutically acceptable salt,solvate, and/or ester thereof.

In yet another embodiment, the present application provides a method forincreasing blood plasma levels of a drug which is metabolized bycytochrome P450 monooxygenase, comprising administering to a patienttreated with said drug, a therapeutically effective amount of a compoundof the present invention, or a pharmaceutically acceptable salt,solvate, and/or ester thereof, and wherein the amount of the compound ofthe present invention administered is effective to inhibit cytochromeP450 monooxygenase.

In yet another embodiment, the present application provides a method forinhibiting cytochrome P450 monooxygenase in a patient comprisingadministering to a patient in need thereof an amount of a compound ofthe present invention, or a pharmaceutically acceptable salt, solvate,and/or ester thereof, effective to inhibit cytochrome P450monooxygenase.

In yet another embodiment, the present application provides a method forinhibiting cytochrome P450 monooxygenase 3A in a patient comprisingadministering to a patient in need thereof an amount of a compound ofthe present invention, or a pharmaceutically acceptable salt, solvate,and/or ester thereof, effective to inhibit cytochrome P450 monooxygenase3A.

In yet another embodiment, the present application provides a method forinhibiting cytochrome P450 monooxygenase comprising contactingcytochrome P450 monooxygenase with an amount of a compound of thepresent invention, or a pharmaceutically acceptable salt, solvate,and/or ester thereof, effective to inhibit cytochrome P450monooxygenase.

In yet another embodiment, the present application provides a method forinhibiting cytochrome P450 monooxygenase 3A comprising contactingcytochrome P450 monooxygenase 3A with an amount of a compound of thepresent invention, or a pharmaceutically acceptable salt, solvate,and/or ester thereof, effective to inhibit cytochrome P450 monooxygenase3A.

In yet another embodiment, the present application provides a method fortreating an HIV infection comprising administering to a patient in needthereof a therapeutically effective amount of a compound of the presentinvention, or a pharmaceutically acceptable salt, solvate, and/or esterthereof, in combination with a therapeutically effective amount of oneor more additional therapeutic agents selected from the group consistingof HIV protease inhibiting compounds, HIV non-nucleoside inhibitors ofreverse transcriptase, HIV nucleoside inhibitors of reversetranscriptase, HIV nucleotide inhibitors of reverse transcriptase, HIVintegrase inhibitors, and CCR5 inhibitors.

In yet another embodiment, the present application provides a method fortreating an HIV infection comprising administering to a patient in needthereof a therapeutically effective amount of a compound of the presentinvention, or a pharmaceutically acceptable salt, solvate, and/or esterthereof, in combination with a therapeutically effective amount of oneor more additional therapeutic agents selected from the group consistingof amprenavir, atazanavir, fosamprenavir, indinavir, lopinavir,ritonavir, nelfinavir, saquinavir, tipranavir, brecanavir, darunavir,TMC-126, TMC-114, mozenavir (DMP-450), JE-2147 (AG1776), L-756423,RO0334649, KNI-272, DPC-681, DPC-684, and GW640385X, DG17, PPL-100,DG35, AG 1859, capravirine, emivirine, delaviridine, efavirenz,nevirapine, (+) calanolide A, etravirine, GW5634, DPC-083, DPC-961,DPC-963, MIV-150, TMC-120, TMC-278 (rilpivirene), efavirenz, BILR 355BS, VRX840773, UK-453061, RDEA806, zidovudine, emtricitabine,didanosine, stavudine, zalcitabine, lamivudine, abacavir, amdoxovir,elvucitabine, alovudine, MIV-210, racivir (±-FTC), D-d4FC,emtricitabine, phosphazide, fozivudine tidoxil, apricitibine (AVX754),amdoxovir, KP-1461, fosalvudine tidoxil (formerly HDP 99.0003),tenofovir, adefovir, curcumin, derivatives of curcumin, chicoric acid,derivatives of chicoric acid, 3,5-dicaffeoylquinic acid, derivatives of3,5-dicaffeoylquinic acid, aurintricarboxylic acid, derivatives ofaurintricarboxylic acid, caffeic acid phenethyl ester, derivatives ofcaffeic acid phenethyl ester, tyrphostin, derivatives of tyrphostin,quercetin, derivatives of quercetin, S-1360, zintevir (AR-177),L-870812, L-870810, MK-0518 (raltegravir), BMS-538158, GSK364735C,BMS-707035, MK-2048, and BA 011, enfuvirtide, sifuvirtide, FB006M, andTRI-1144, AMD-070, an entry inhibitor, SP01A, BMS-488043, BlockAide/CR,a G6PD and NADH-oxidase inhibitor, immunitin, aplaviroc, vicriviroc,maraviroc, maraviroc, PRO-140, INCB15050, PF-232798 (Pfizer), CCR5mAb004, BAS-100, SPI-452, REP 9, SP-01A, TNX-355, DES6, ODN-93, ODN-112,VGV-1, PA-457 (bevirimat), Ampligen, HRG214, Cytolin, VGX-410, KD-247,AMZ 0026, CYT 99007A-221 HIV, DEBIO-025, BAY 50-4798, MDXO10(ipilimumab), PBS119, ALG 889, and PA-1050040 (PA-040).

In yet another embodiment, the present application provides a method fortreating an HCV infection comprising administering to a patient in needthereof a therapeutically effective amount of a compound of the presentinvention, or a pharmaceutically acceptable salt, solvate, and/or esterthereof, in combination with a therapeutically effective amount of oneor more additional therapeutic agents selected from the group consistingof pegylated rIFN-alpha 2b, pegylated rIFN-alpha 2a, rIFN-alpha 2b,rIFN-alpha 2a, consensus IFN alpha (infergen), feron, reaferon, intermaxalpha, r-IFN-beta, infergen+actimmune, IFN-omega with DUROS, locteron,albuferon, rebif, Oral interferon alpha, IFNalpha-2b XL, AVI-005,PEG-Infergen, and pegylated IFN-beta, rebetol, copegus, viramidine(taribavirin), NM-283, valopicitabine, R1626, PSI-6130 (R1656), HCV-796,BILB 1941, XTL-2125, MK-0608, NM-107, R7128 (R4048), VCH-759, PF-868554,GSK625433, SCH-503034 (SCH-7), VX-950 (telaprevir), BILN-2065,BMS-605339, ITMN-191, MX-3253 (celgosivir), UT-231B, IDN-6556, ME 3738,LB-84451, MitoQ, benzimidazole derivatives, benzo-1,2,4-thiadiazinederivatives, phenylalanine derivatives, A-831, A-689, zadaxin,nitazoxanide (alinea), BIVN-401 (virostat), PYN-17 (altirex),KPE02003002, actilon (CPG-10101), KRN-7000, civacir, GI-5005, ANA-975,XTL-6865, ANA 971, NOV-205, tarvacin, EHC-18, NIM811, DEBIO-025,VGX-410C, EMZ-702, AVI 4065, Bavituximab, Oglufanide, and VX-497(merimepodib).

In still yet another embodiment, the present application provides forthe use of a compound of the present invention, or a pharmaceuticallyacceptable salt, solvate, and/or ester thereof, for the preparation of amedicament for inhibiting cytochrome P450 monooxygenase in a patient.

In still yet another embodiment, the present application provides forthe use of a compound of the present invention, or a pharmaceuticallyacceptable salt, solvate, and/or ester thereof, for the preparation of amedicament for treating an HIV infection.

In still yet another embodiment, the present application provides forthe use of a compound of the present invention, or a pharmaceuticallyacceptable salt, solvate, and/or ester thereof, for the preparation of amedicament for increasing blood plasma levels of the drug which ismetabolized by cytochrome P450 monooxygenase.

In still yet another embodiment, the present application provides forthe use of a compound of the present invention, or a pharmaceuticallyacceptable salt, solvate, and/or ester thereof, for the preparation of amedicament for improving the pharmacokinetics of a drug which ismetabolized by cytochrome P450 monooxygenase.

EXAMPLES Preparation of Example A

Compound 2

To a solution of Compound 1 (ritonavir) (1.8 g, 2.5 mmol) in1,2-dichloroethane (15 mL) was added 1,1′-thiocarbonyldiimidazole (890mg, 5.0 mmol). The mixture was heated at 75° C. for 6 hours and cooledto 25° C. Evaporation under reduced pressure gave a white solid.Purification by flash column chromatography (stationary phase: silicagel; eluent: EtOAc) gave Compound 2 (1.6 g). m/z: 831.1 (M+H)⁺.

Example A

To the refluxing solution of tributyltin hydride (0.78 mL, 2.9 mmol) intoluene (130 mL) was added a solution of Compound 2 (1.6 g, 1.9 mmol)and 2,2′-azobisisobutyronitrile (31 mg, 0.19 mmol) in toluene (30 mL)over 30 minutes. The mixture was heated at 115° C. for 6 hours andcooled to 25° C. Toluene was removed under reduced pressure.Purification by flash column chromatography (stationary phase: silicagel; eluent: hexane/EtOAc=1/10) gave Example A (560 mg). m/z: 705.2(M+H)⁺. ¹H-NMR (CDCl₃) δ 8.79 (1H, s), 7.82 (1H, s), 7.26-7.05 (10H, m),6.98 (1H, s), 6.28 (1H, m), 6.03 (1H, m), 5.27 (1H, m), 5.23 (2H, s),4.45-4.22 (2H, m), 4.17 (1H, m), 3.98 (1H, m), 3.75 (1H, m), 3.25 (1H,m), 2.91 (3H, s), 2.67 (4H, m), 2.36 (1H, m), 1.6-1.2 (10H, m), 0.85(6H, m).

Preparation of Example B

Example B

To a solution of Compound 1 (ritonavir) (98 mg, 0.136 mmol) indichloromethane (4 mL) was added Dess-Martin periodinane (61 mg, 0.143mmol). The mixture was stirred at room temperature for 6 hours. Themixture was then partitioned between dichloromethane and brine, thedichloromethane layer was separated, dried and evaporated to dryness.Purification with CombiFlash® (stationary phase: silica gel; eluent:40-80% EtOAc/Hexane gradient) gave Example B as a white solid. Example Bwas further purified by trituration with MeOH/hexane to give 83 mg of awhite solid. m/z: 719 (M+H)⁺.

Preparation of Example C

Compound 3

Compound 3 was prepared according to the procedures of J. Med. Chem.1998, 41, 602, herein incorporated by reference in its entirety for allpurposes.

Compound 4

A flask was charged with cyclopropylamine (8.2 mL, 117.8 mmol) at roomtemperature. A solution of Compound 3 (1 g, 4.71 mmol) in MeCN (8.5 mL)was added dropwise over 5 min. to produce a clear yellow solution thatwas allowed to stand at room temperature overnight. Volatiles wereremoved in vacuo, and the resulting residue was purified via silica gelchromatography (gradient elution, 0 to 50% EtOAc/hexane) to afford 0.65g (70%) of 4 as a yellow liquid (LC/MS m/z 197 (M+H)⁺; 218 (M+Na)⁺).

Compound 5

Compound 5 was purchased from Aldrich or alternatively preparedaccording to the procedures of J. Org. Chem. 1994, 59, 1937, hereinincorporated by reference in its entirety for all purposes.

Compound 6

To a solution of Compound 4 in DCM (3 mL) at room temperature was added5 (0.1 mL, 0.695 mmol). The resulting clear solution was allowed tostand at room temperature for 2 h. The solvent was removed in vacuo, andthe residue was chromatographed directly using silica gel chromatography(gradient elution, 0 to 50% EtOAc/hexane) to produce 0.218 g (89%) of 6(LC/MS m/z 354 (M+H)⁺; 729 (2M+Na)⁺) as a colorless glass.

Compound 7

Compound 6 was taken up in THF (5 mL) at room temperature, and LiOH (1 Min H₂O) was added. The resulting reaction mixture was then stirredvigorously for 1.5 h. The reaction mixture was acidified with 1 M HCl toa pH of 3 (monitored using pH test strips). The acidified reactionmixture was then extracted several times with EtOAc. The combinedorganic phases were washed with brine, dried over anhydrous Na₂SO₄, andconcentrated in vacuo to produce 0.20 g (quantitative yield) of 7 (LC/MSm/z 340 (M+H)⁺) as a colorless film. This material was used withoutfurther purification.

Example C

Compounds 7 (0.034 g, 0.100 mmol) and 8, (0.034 g, 0.083 mmol) werediluted in THF (2 mL) at room temperature. To the resulting solutionwere added N,N-diisopropylethylamine (0.022 mL, 0.125 mmol), EDC (0.018mL, 0.099 mmol) and HOBt (0.013 g, 0.099 mmol). The solution was thenallowed to stand overnight at room temperature. The solvent was removedin vacuo and the residue was taken up in MeCN (0.5 mL) and passedthrough an Acrodisc LC13 PVDF filter (0.45 μM) prior to purification bypreparatory HPLC to afford 0.043 g (71%) of Example C as a fluffy whitesolid. (¹H-NMR (300 MHz, CDCl₃) δ 8.79 (s, 1H); 7.82 (s, 1H); 7.27-7.02(m, 10H); 6.81 (s, 1H); 5.97 (br d, J=8.7 Hz, 1H); 5.76 (br d, J=7.2 Hz,1H); 5.21 (dt, J=7.5, 12.6 Hz, 2H); 5.02, br d, J=8.4 Hz, 1H); 4.58 (s,2H); 4.16 (m, 1H); 3.99 (br t, J=6.6 Hz, 1H); 3.79 (m, 1H); 3.27 (pent,J=6.6 Hz, 1H); 2.85-2.50 (m, 3H); 2.23 (m, 1H); 1.82 (br s, 2H);1.60-1.22 (m, 4H); 1.36 (d, J=6.6 Hz, 6H); 0.91 (d, J=6.6 Hz, 3H);0.90-0.7 (m, 4H); 0.80 (d, J=6.6 Hz, 3H); LC/MS m/z 731 (M⁺)).

Preparation of Examples D-I

Compound 9

Compound 9 was prepared according to the procedures of J. Med. Chem.1998, 41, 602.

Compound 10

The structures of Compound 10 were prepared according to the proceduresof J. Med. Chem. 1998, 41, 602.

Compound 11

The structures of Compound 11 were purchased from Aldrich or preparedaccording to the procedures of J. Org. Chem. 1994, 59, 1937.

Compound 12

Method 1: To a solution of Compound 9 (0.8 mmol) in THF (2 mL) was addeda carbamate of Compound 10 (0.6 mmol), followed by DMAP (16 mg) andtriethylamine (0.25 mL). The resulting mixture was heated at 70° C. fortwo hours and diluted with EtOAc. The organic phase was separated, andwashed sequentially with saturated aqueous Na₂CO₃, water, and brine,then concentrated under reduced pressure. Purification of the residue byflash column chromatography (silica gel, 1/1-1/3 hexanes/EtOAc gradient)gave compounds of Structure 12.

Method 2: To a solution of Compound 9 (2.4 mmol) in CH₂Cl₂ (2 mL) wasadded an isocyanate of Compound 11 (2 mmol). The resulting mixture wasstirred for 4 hours and concentrated. Purification of the residue byflash column chromatography (silica gel, hexane/EtOAc 1/1-1/3) gavestructures of Compound 12.

Compound 13

To a solution of structures of Compound 12 (1.8 mmol) in dioxane. (8 mL)and water (8 mL) was added sodium hydroxide (3.6 mmol). The resultingreaction mixture was stirred for 1 hour and acidified with HCl indioxane (3.6 mmol). The reaction mixture was extracted with EtOAc andthe organic phase was dried with anhydrous MgSO₄. Concentration of thedried organic phase gave structures of Compound 13.

Compound 16

To a solution of Compound 15 (obtained commercially from Molekula) (17mmol) in DCM (40 mL) was added Compound 14 (19 mmol), followed bytriethylamine (26 mmol). The resulting reaction mixture was stirred for12 hour and concentrated under reduced pressure. The reaction mixturewas diluted with EtOAc and washed sequentially with saturated aqueousNa₂CO₃, water, and brine. The solvent was removed under reducedpressure. Purification of the residue by flash column chromatography(silica gel, eluent: hexanes/EtOAc=1/1) gave Compound 16 (4.7 g).

Compound 17

Compound 17 was prepared according to the procedures of Tetrahedron1997, 53, 4769, herein incorporated by reference in its entirety for allpurposes.

Compound 18

Compound 18 was prepared according to the procedures of J. Org. Chem.1987, 52, 3759, herein incorporated by reference in its entirety for allpurposes.

Compound 19

A suspension of Compound 18 (7.4 mmol) in THF (200 mL) was heated underreflux until a clear solution was obtained. The solution was cooled to−78° C. and n-butyllithium (14.8 mmol) was added dropwise to provide asolution of the dianion of sulfone 18.

To a DIBAL-H solution (7.8 mmol) at 0° C. was added a solution of MeOH(7.8 mmol) in THF (5 mL). The mixture was stirred for 5 minutes andcooled to −78° C. A solution of Compound 17 (6.6 mmol) in THF (5 mL) wasadded to the above DIBAL-H/MeOH solution, and the resulting reactionmixture was stirred for another 5 minutes. The resulting solution ofaldehyde complexes was transferred to solution of the dianion of sulfone18. The resulting mixture was stirred at −78° C. for 30 minutes,quenched with an aqueous solution of NH₄Cl, and warmed to 25° C. Themixture was then extracted with EtOAc, and concentrated to give Compound19 as a mixture of diastereomers. (m/z 737.3 (M+Na)⁺.

Example 20

To a solution of Compound 19 in DCM (20 mL) was added Ac₂O (1.5 mL),followed by pyridine (3 mL). The resulting mixture was stirred for 12hours and concentrated. The concentrate was dissolved in MeOH (30 mL)and cooled to 0° C. NaH₂PO₄ (4.9 g) was added to the solution, followedby freshly prepared Na—Hg (6%, 6 g). The resulting mixture was warmed to25° C. and stirred for 12 hours. Water (50 mL) was then added, and themixture was filtered and concentrated. The concentrate was diluted withEtOAc and washed with brine. The organic phase was concentrated.Purification by flash column chromatography (silica gel, eluent:hexanes/EtOAc=10/1) gave Compound 20 (1.4 g).

Compound 21

To liquid ammonia (25 mL) at −33° C. was added a solution of Compound 20(1.4 g) in THF (2.5 mL). Sodium was slowly added until the blue color ofthe solution persisted. The resulting mixture was stirred for 1 hour.Solid NH₄Cl (6 g) was then added slowly, the mixture was warmed to 25°C. and the ammonia was evaporated. The mixture was diluted with EtOAc,and washed sequentially with water and brine. The solvent was removedunder reduced pressure. Purification of the resulting residue by flashcolumn chromatography (silica gel, eluent: hexanes/EtOAc=5/1) gaveCompound 21 (1.15 g).

Compound 22

A mixture of Compound 21 (1.15 g) and 10% Pd/C (160 mg) in MeOH (20 mL)was hydrogenated for 12 hours. CELITE was added and the resultingmixture was stirred for 5 minutes. The mixture was then filtered andconcentrated to give an intermediate (1 g). The intermediate (700 mg)was dissolved in DCM (20 mL) and TFA (4 mL), and the resulting mixturewas stirred for 4 hours, then concentrated under reduced pressure. Theconcentrated mixture was diluted with EtOAc, and washed sequentiallywith saturated aqueous Na₂CO₃, water, and brine. Concentration of thewashed EtOAc mixture gave Compound 22 (420 mg).

Compound 8

To a solution of Compound 22 (1.57 mmol) in CH₃CN (16 mL) was addedCompound 16 (1.57 mmol), followed by diisopropylethylamine (3.14 mmol).The resulting mixture was stirred for 12 hours. The mixture was thendiluted with EtOAc, and washed sequentially with saturated aqueousNa₂CO₃, water and brine. Purification by reverse-phase HPLC (PhenomenexSynergi® Comb-HTS column, eluent: 25%-100% CH₃CN in water) gave Compound8 (460 mg).

Example D

To the solution of Compound 13a (R═H, 0.08 mmol) and Compound 8 (0.06mmol) in THF (1 mL) were added HOBt (15 mg), EDC (26 mg), anddisopropylethylamine (0.25 mL). The mixture was stirred for 12 hours andconcentrated. Purification by reverse phase HPLC (Phenomenex Synergi®Comb-HTS column, eluent: 25%-100% CH₃CN in water) gave Example D (27mg). m/z 663.1 (M+H)⁺. ¹H-NMR (CDCl₃) δ 8.79 (1H, s), 7.83 (1H, s),7.25-7.04 (10H, m), 6.98 (1H, s), 6.25 (1H, m), 5.25 (3H, m), 4.40 (2H,s), 4.12 (1H, m), 3.8 (3H, m), 3.22 (1H, m), 2.95 (3H, s), 2.70 (4H, m),1.60 (4H, m), 1.26 (6H, d, J=7 Hz).

Example E

Example E was prepared following the procedure for Example D (30 mg),except that Compound 13b was used instead of Compound 13a. m/z 677.1(M+H)⁺.

Example F

Compound F was prepared following the procedure for Example D (40 mg),except that Compound 13c was used instead of Compound 13a. m/z 691.2(M+H)⁺. ¹H-NMR (CDCl₃) δ 8.80 (1H, s), 7.83 (1H, s), 7.25-7.06 (10H, m),6.98 (1H, s), 6.35 (1H, m), 6.23 (1H, m), 5.24 (2H, s), 5.12 (1H, m),4.34 (2H, s), 4.10 (2H, m), 3.78 (1H, m), 3.23 (1H, m), 2.90 (3H, s),2.68 (4H, m), 1.90 (2H, m), 1.7-1.4 (4H, m), 1.36 (6H, d, J=7.0 Hz),0.90 (3H, t, J=7.3 Hz)

Example G

Example G was prepared following the procedure for Example D (84 mg),except that Compound 13d was used instead of Compound 13a. m/z 783.2(M+H)⁺.

Example H

Example H was prepared following the procedure for Example D (90 mg),except that Compound 13e was used instead of Compound 13a. m/z 763.2(M+H)⁺.

Example I

Example H (24 mg) was dissolved in TFA (2 mL) and the mixture wasstirred for 12 hours, then concentrated, Purification by reverse phaseHPLC (Phenomenex Synergi® Comb-HTS column, eluent: 25%-100% CH₃CN inwater) gave Example I (14 mg). m/z 707.2 (M+H)⁺. ¹H-NMR (CDCl₃) δ 8.82(1H, s), 7.85 (1H, s), 7.26-7.04 (10H, m), 7.0 (1H, s), 5.25 (2H, s),4.86 (1H, m), 4.56 (1H, m), 4.37 (2H, m), 4.13 (1H, m), 4.06 (1H, m),3.86 (1H, m), 3.32 (1H, m), 2.99 (3H, s), 2.8-2.6 (4H, m), 1.6-1.4 (4H,m), 1.37 (6H, m), 1.15 (3H, m).

Preparation of Example J

Example J

Compound 23 was prepared following the procedure for Compound 13, withthe exception that methyl 3-isocyanatopropionate was used instead ofCompound 11.

Example J was prepared following the procedure for Example D (37 mg),except that Compound 23 was used instead of Compound 13a. m/z 677.2(M+H)⁺.

Preparation of Example K

Example K Compound 5a

Compound 5a was prepared following the literature procedure of Synthesis823, 1976, herein incorporated by reference in its entirety for allpurposes.

Compound 5b

To the solution of Compound 5a (700 mg, 3.9 mmol) in THF (10 mL) wasadded water (69 μL, 3.9 mmol), followed by triphenylphosphine (1.06 g,4.0 mmol). The mixture was stirred for 12 hours. Solvents were removedand the mixture was dried to give Compound 5b, which was used for nextstep without further purification.

Compound 5c

To a solution of triphosgene (110 mg, 0.37 mmol) in CH₂Cl₂ (2 mL) at 0 Cwas added a solution of Compound 5b (1 mmol) and iPrNEt₂ (0.38 mL, 2.2mmol) in CH₂Cl₂ (3.5 mL) over 30 minutes period. The mixture was stirredfor 30 minutes, and a solution of amino N-methyl leucine methyl esterHCl salt (182 mg, 1 mmol) and iPrNEt₂ (0.34 mL, 2.2 mmol) in CH₂Cl₂ (2mL) was added. The mixture was stirred for 12 hours, and diluted withEtOAc. The solution was washed with sat. Na₂CO₃ (2×), water (2×), andbrine, and dried over Na₂SO₄. Concentration and purification with silicagel flash column gave Compound 5c (300 mg).

Compound 5d

Compound 5d was prepared following the procedure for Compound 13, withthe exception that Compound 5c was used instead of Compound 12.

Example K

Example K was prepared following the procedure for Example D (7 mg),except that Compound 5d was used instead of Compound 13a. m/z 705.2(M+H)⁺. ¹H-NMR (CDCl₃) δ 8.8 (1H, m), 7.86 (1H, s), 7.26-6.8 (11H, m),6.10 (1H, m), 5.5-5.10 (4H, m), 4.46 (2H, m), 4.2-3.75 (3H, m), 3.25(1H, m), 2.82/2.4 (3H), 2.8-2.5 (4H, m), 2.17 (1H, m), 1.7-1.2 (10H, m),0.8 (6H, m).

Preparation of Example L

Example L

To a solution of Compound 22 (1.57 mmol) in CH₃CN (16 mL) was addedCompound 16 (3.14 mmol), followed by triethylamine (4.71 mmol). Theresulting mixture was stirred for 12 hours. The reaction mixture wasdiluted with EtOAc and washed sequentially with saturated aqueousNa₂CO₃, water, and brine. The solvent was removed under reducedpressure. Purification of the residue by flash column chromatography(silica gel, eluent: hexanes/EtOAc=1/1) gave Example L (460 mg). m/z551.2 (M+H)⁺. ¹H-NMR (CDCl₃) δ 8.81 (2H, s), 7.85 (2H, s), 7.26-7.0(10H, m), 5.24 (4H, s), 4.50 (2H, m), 3.87 (2H, m), 2.73 (4H, m),1.4-1.2 (4H, m).

Alternate Preparation of Compound 22

Compound 25

Compound 25 was prepared following the literature procedure described inJ. Org. Chem. 1996, 61, 444 (herein incorporated by reference in itsentirety), except that the L-isomer was prepared instead of theD-isomer.

Compound 26

A mixture of Compound 25 (7.4 g) and 1,1′-thiocarbonyldiimidaxole (4.5g) in THF (260 mL) was heated at 65° C. for 54 hours. Solvent wasremoved from the mixture under reduced pressure. Purification by flashcolumn chromatography (silica gel, hexanes/EtOAc=1/1) gave Compound 26(7.33 g).

Compound 27

The mixture of Compound 26 (7.3 g) and triethylphosphite (100 mL) washeated at 160° C. for 4 hours. Excess reagents were removed underreduced pressure. Purification by flash column chromatography (silicagel, hexanes/EtOAc=3/1) gave Compound 27 (5 g).

Compound 22

A mixture of Compound 27 (250 mg) in i-PrOH/EtOAc (5 mL/5 mL) washydrogenated for 14 hours in the presence of 10% Pd/C (75 mg). CELITEwas added to the mixture, and the mixture was stirred for 5 minutes.Filtration and evaporation of solvents gave Compound 22 (116 mg).

The skilled practitioner will recognize that the procedure outlined inScheme 12 can be used to prepare a variety of 1,4-substituted1,4-diamines analogous to Compound 22. For example, an amine-protected2,3-dihydroxy-1,4-diamine analogous to Compound 25 can be prepared:

Analogs of Compound 25

wherein L³, A, Ar, and P are as defined herein, and protecting group “P”is any amine protecting group described in described in ProtectiveGroups in Organic Synthesis, Theodora W. Greene and Peter G. M. Wuts(John Wiley & Sons, Inc., New York, 1999, ISBN 0-471-16019-9), which isherein incorporated by reference in its entirety for all purposes. Theanalogs of Compound 25 can then be transformed, according to the methodsoutlined in Scheme 12, to form analogs of Compound 26:

Analogs of Compound 26

analogs of Compound 27:

Analogs of Compound 27; and

analogs of Compound 22:

Analogs of Compound 22 Preparation of Examples M and N

Compound 29

Compound 28 was prepared using a procedure similar to that used toprepare Compound 6 (described in Scheme 4) except that Compound 9 wasused instead of Compound 4.

To a solution of Compound 28 (0.757 g, 2.31 mmol) in THF (9 mL) at roomtemperature was added freshly prepared 1M LiOH (4.6 mL, 4.6 mmol). After1.5 h, 1 M HCl (7 mL, 7 mmol) was added and the reaction mixtureextracted thoroughly with EtOAc (5×15 mL). The combined organic layerswere dried over anhydrous Na₂SO₄ and the volatiles removed in vacuo toafford 0.677 g (93%) of Compound 29 as a colorless glassy solid (LC/MSm/z 314.0 (M+H)⁺) that was used in the following procedures withoutfurther purification.

Compound 30

Compound 30 was purchased from Aldrich Chemical Co., and used withoutfurther purification.

Compound 31

To a solution of Compound 30 (8.25 g, 80 mmol) in MeOH (50 mL), wasadded benzaldehyde (8.1 mL, 80 mmol) and the resulting solution wasallowed to stir at room temperature. After 2 h, the reaction mixture wascooled to 0° C. and NaBH₄ (3.33 g, 88 mmol) was added in portions. Afterallowing the reaction mixture to warm to room temperature over 2 h,glacial acetic acid (2 mL) was added. The resulting viscous solution wasconcentrated in vacuo. EtOAc and H₂O (50 mL each) were added and theaqueous phase was extracted with EtOAc. The combined organic phases werewashed with saturated NaHCO₃, brine, and concentrated in vacuo. Theresulting material was taken up in THF (25 mL) and H₂O (25 mL) at roomtemperature and Boc₂O (15.1 g, 69.2 mmol) was added to produce an opaquesuspension that was stirred vigorously for 2 h at room temperature. THFwas removed in vacuo, and the aqueous layer was extracted with EtOAc.The combined organic layers were washed with brine and dried overanhydrous MgSO₄ and concentrated in vacuo. Chromatography on SiO₂ (3/1Hex/EtOAC) afforded 18.5 g (79%) of Compound 31 as a colorless oil(LC/MS m/z 293.9 (M+H)⁺.

Compound 32

Compound 31 (5.95 g, 20.3 mmol) and Et₃N (9.9 mL, 71 mmol) were dilutedin DMSO (65 mL) and allowed to age at room temperature for 30 min beforecooling to 0° C. Pyridine.SO₃ was added in one portion and the reactionmixture was maintained at 5° C. to prevent freezing. After 45 min, thereaction mixture was poured into icewater and extracted with EtOAc. Thecombined organic layers were washed with saturated NaHCO₃, H₂O, anddried over anhydrous MgSO₄ prior to concentration in vacuo (bathtemperature 25° C.) to produce 4.39 g (74%) of Compound 32 as a clear,yellow colored oil that was used without further purification. ¹H-NMR(CDCl₃, 300 MHz) 6 (major rotamer) 9.36 (br s, 1H); 5.01 (d, J=15 Hz,1H); 4.12 (d, J=15 Hz, 1H); 3.45 (m, 1H); 2.04-1.88 (m, 1H); 1.80-1.58(m, 1H); 1.54-1.20 (m, 2H); 1.47 (s, 9H); 0.91 (t, J=7.2 Hz, 3H). (minorrotamer) 9.46 (br s, 1H); 4.71 (d, J=15 Hz, 1H); 4.20 (d, J=15 Hz, 1H);3.78 (m, 1H); 2.04-1.88 (m, 1H); 1.80-1.58 (m, 1H); 1.54-1.20 (m, 2H);1.47 (s, 9H); 0.91 (t, J=7.2 Hz, 3H)

Compound 34

A suspension of Compound 33 (6.23 g, 16.6 mmol) in THF (500 mL) washeated under reflux until a homogeneous solution was obtained. Thesolution was cooled to −78° C. and 1.6M n-BuLi (19.7 mL, 31.5 mmol) wasintroduced to produce a clear yellow solution. Meanwhile, DIBAL-OMe wasprepared by dilution of DIBAL-H (1M in hexanes, 18.1 mL, 18.1 mmol) inTHF (8 mL) and cooling to 0° C. prior to addition of MeOH (0.73 mL, 18.1mmol). This solution was allowed to age while Compound 32 (4.39 g, 15.1mmol) was diluted in THF (15 mL) and cooled to −78° C. The DIBAL-OMesolution was cannulated to the solution of Compound 32 and allowed toage for 5 min prior to cannulation to the sulfur dianion solution. Theresulting clear yellow solution was allowed to age at −78° C. for 1 h.The reaction was quenched by addition of saturated NH₄Cl (100 mL) at−78° C. and allowed to warm to room temperature. Water was added untilall precipitated solids were dissolved and the layers separated. The THFlayer was concentrated in vacuo while the aqueous layer was extractedwith EtOAc. The recombined organic layers were washed with brine, andthe resulting emulsion was treated with solid NaOH until homogeneousbilayers resulted. The aqueous layer was extracted with EtOAc and thecombined organics dried over anhydrous Na₂SO₄. Concentration in vacuoproduced 9.57 g (95%) of Compound 34 as an amorphous white solid (LC/MSm/z: 689.3 (M+Na)⁺) that was used in the following procedures withoutfurther purification.

Compound 35

Crude Compound 34 was suspended in CH₂Cl₂ (65 mL) followed by additionof pyridine (6.7 mL, 83 mmol) and acetic anhydride (3.5 mL, 36.5 mmol).The resulting solution was allowed to age at room temperature overnight.MeOH (6 mL) was added and after 10 min, the reaction was poured intobrine. Addition of water produced a bilayer that was separated and theaqueous phase was repeatedly extracted with CH₂Cl₂. The combined organiclayers were dried over anhydrous MgSO₄ and concentrated in vacuo toproduce 8.95 g (88%) of a white solid that was immediately taken up inMeOH (100 mL). Na₂HPO₄ (11.4 g, 80.3 mmol) was added and the resultingslurry was cooled to 0° C. prior to addition of Na—Hg (6%, 14.5 g, 37.8mmol) in portions. After aging at room temperature overnight, H₂O (30mL) was added and the reaction was filtered through a celite pad. MeOHwas removed in vacuo and the aqueous residue was extracted with EtOAc.The combined organic layers were washed with brine, dried over anhydrousMgSO₄ and concentrated in vacuo to a yellow oil that was purified bychromatography on SiO₂ (0-15% EtOAc/hexanes) to afford 2.14 g (34%) ofCompound 35 as a colorless oil (LC/MS m/z: 531.2 (M+Na)⁺).

Compound 36

Compound 35 (1.73 g, 3.4 mmol) was diluted in MeOH (7.5 mL) and 10% Pd/C(0.36 g, 0.34 mmol) was added. The atmosphere was replaced with a H₂balloon and the reaction mixture allowed to age at room temperature.After 2 h, the reaction mixture was filtered through a pad of celite,the filtrate was washed several times with MeOH, and the combinedorganic layers were concentrated in vacuo to afford 1.45 g (83%) ofCompound 36 as a colorless oil (LC/MS m/z: 533.2 (M+Na)⁺) that was usedin the following procedures without further purification.

Compound 37

Compound 36 (0.528 g, 1.03 mmol) was diluted in THF (3 mL) and added toliquefied ammonia (approx. 20 mL) at −35° C. Small pieces of Na wereadded until a blue color persisted. After 1.5 h, solid NH₄Cl was addedin portions until the remaining Na was destroyed and the ammonia wasallowed to escape at ambient temperature. Water and EtOAc (20 mL each)were added, and the aqueous layer was extracted with EtOAc. The combinedorganic layers were washed with brine, dried over Na₂SO₄ andconcentrated in vacuo to afford 0.395 g (91%) of Compound 37 as anamorphous white solid that was used without further purification in thefollowing procedures (LC/MS m/z: 421.1 (M+H)⁺; 443.2 (M+Na)⁺).

Compound 38

Compound 37 (0.362 g, 0.861 mmol) was diluted in CH₂Cl₂ (3.2 mL).Trifluoroacetic acid (0.8 mL) was added and the clear solution wasallowed to age overnight. Following concentration in vacuo, the residuewas azeotroped with toluene several times to remove residual TFA. 0.382g (99%) of the bis-trifluoroacetate salt of Compound 38 was collected asa colorless oil that was used without further purification (LC/MS m/z:221.1 (M+H)⁺).

Compounds 39 and 40

Compound 38 (0.382 g, 0.852 mmol) was diluted in MeCN (10 mL) andN,N-diisopropylethylamine (0.60 mL, 3.41 mmol) was added, followed by asolution of Compound 16 in MeCN (1.5 mL). The clear, yellow solution wasallowed to age at room temperature for 4 h and the volatiles wereremoved in vacuo. The residue was taken up in a 3/1 CHCl₃/IPA (v/v, 13mL) and treated with saturated Na₂CO₃ (3 mL). The resulting suspensionwas diluted with H₂O (3 mL), and the aqueous phase thoroughly extractedwith 3/1 CHCl₃/IPA. The combined organic layers were dried over a 3/2(w/w) mixture of anhydrous Na₂SO₄/anhydrous Na₂CO₃ and concentrated invacuo. Chromatography on SiO₂ (0-20% MeOH/CH₂Cl₂) afforded 0.043 g (14%)of Compound 39 as a colorless film (LC/MS m/z: 362.1 (M+H)⁺) and 0.105 g(34%) of Compound 40 as a colorless film (LC/MS m/z: 362.1 (M+H)⁺).

Example M

A flask was charged with Compound 39 (0.048 g, 0.133 mmol) and Compound29 was added as a 0.2 M solution in THF (0.8 mL, 0.160 mmol). THF (1 mL)was added, followed by DIPEA (0.026 mL, 0.145 mmol), HOBt (0.022 g,0.160 mmol) and finally EDC (0.028 mL, 0.160 mmol). The clear, colorlesssolution was allowed to age overnight. Volatiles were removed in vacuoand the residue chromatographed on SiO₂ (0-20% MeOH/CH₂Cl₂). Fractionscontaining the desired compound were concentrated in vacuo and submittedto preparatory LC/MS purification to afford 0.018 g (20%) of Example Mas a colorless film LC/MS m/z: 657.2 (M+H)⁺; ¹H-NMR (CDCl₃, 300 MHz) δ8.95 (s, 1H); 7.88 (br s, 1H); 7.27-7.04 (m, 5H); 7.04 (s, 1H);6.60-6.20 (m, 2H); 5.22 (m, 2H); 5.12 (d, J=9.3 Hz, 1H); 4.50 (m, 2H);4.01 (br s, 1H); 3.83 (m, 2H); 3.38 (m, 1H); 3.10-2.94 (m, 3H); 2.74 (m,2H); 2.23 (m, 1H); 1.64-1.15 (m, 8H); 1.40 (d, J=6.9 Hz, 6H); 0.96 (m,6H); 0.83 (t, J=6.9 Hz, 3H).

Example N

Example N was prepared using procedures similar to those used to prepareExample M, using the following reagents: Compound 40 (0.055 g, 0.152mmol); Compound 29 (0.92 mL of 0.2 M THF solution, 0.183 mmol); THF (1mL); DIPEA (0.040 mL, 0.228 mmol); HOBt (0.025 g, 0.182 mmol); EDC(0.032 mL, 0.182 mmol). 0.087 g (87%) of Example N was isolated as acolorless film (LC/MS m/z: 657.2 (M+H)⁺; ¹H-NMR CDCl₃, 300 MHz) δ 8.84(s, 1H); 7.86 (s, 1H); 7.27-7.04 (m, 5H); 7.04 (s, 1H); 6.28 (br s, 1H);6.12 (br s, 1H); 5.25 (m, 2H); 5.11 (d, J=9.0 Hz, 1H); 4.62-4.32 (m,2H); 4.19 (m, 1H); 4.01 (br s, 1H); 3.53 (m, 1H); 3.10-2.90 (m, 3H);2.72 (d, J=6.0 Hz, 2H); 2.29 (m, 1H); 1.65-1.18 (m, 8H); 1.39 (d, J=6.9Hz, 6H); 1.00-0.78 (m, 9H).

Preparation of Examples O and P

Compound 41

Compound 41 was prepared following the procedure described in J. Org.Chem. 1996, 61, 444-450.

Compound 42

A mixture of Compound 41 (1.73 g, 3 mmol) and1,1′-thiocarbonyldiimidazole (1.14 g, 6.1 mmol) in THF (60 mL) washeated at 65° C. for 72 hours. Solvent was removed under reducedpressure. The mixture was diluted with EtOAc, and washed successivelywith 1N HCl, water, and brine, and dried over MgSO₄. Purification byflash column chromatography (silica gel, hexanes/EtOAc=1/1) gaveCompound 42 (980 mg). m/z: 611.1 (M+H)⁺.

Compound 43

A mixture of Compound 42 (980 mg) and triethyl phosphite (10 mL) washeated at 160° C. for 14 hours. The excess reagents were removed underreduced pressure. Recrystallization from a mixture of hexanes (11 mL)and EtOAc (3.6 mL) gave Compound 57 (580 mg). m/z: 557.3 (M+Na)⁺.

Compound 44

A mixture of Compound 43 (580 mg) in i-PrOH/EtOAc (12 mL/12 mL) washydrogenated under high pressure (100 psi) for 24 hours in the presenceof 10% Pd/C (200 mg). Celite was added and the mixture was stirred for 5minutes. Filtration and evaporation gave Compound 44 (285 mg). m/z:269.1 (M+H)⁺.

The skilled practitioner will recognize that the procedure outlined inScheme 16 can be used to prepare a variety of 1,4-substituted1,4-diamines analogous to Compound 44. For example, an amine-protected2,3-dihydroxy-1,4-diamine analogous to Compound 41 can be prepared:

Analogs of Compound 41

wherein L³, A, Ar, and P are as defined herein, and protecting group “P”is any amine protecting group described in described in ProtectiveGroups in Organic Synthesis, Theodora W. Greene and Peter G. M. Wuts(John Wiley & Sons, Inc., New York, 1999, ISBN 0-471-16019-9). Theanalogs of Compound 41 can then be transformed, according to the methodsoutlined in Scheme 16, to form analogs of Compound 42:

Analogs of Compound 42

analogs of Compound 43:

Analogs of Compound 43; and

analogs of Compound 44:

Analogs of Compound 44

It will also be recognized that stereochemical configurations other thanthose shown (i.e., enantiomers or diasteriomers) can be prepared by theselection of analogs of Compound 41 having the appropriatestereochemical configuration at the chiral centers.

Compound 46

To the solution of Compound 45 (950 mg, 3.5 mmol) in CH₃CN (36 mL) at 0°C. was added Compound 16 (892 mg, 3.2 mmol), followed bydiisopropylethylamine (1.2 mL, 7 mmol). The mixture was stirred for 12hours at 25° C. The mixture was diluted with EtOAc, and washedsuccessively with saturated Na₂CO₃, water, and brine. Purification byflash column chromatography (silica gel, 100% EtOAc to CH₂Cl₂/MeOH=4/1)gave Compound 46 (770 mg). m/z: 410.1 (M+H)⁺.

The skilled practitioner will recognize that the procedure outlined inScheme 17 can be used to prepare a variety of compounds analogous toCompound 46. For example, 1,4-diamines analogous to Compound 44 can beprepared as discussed above:

Analogs of Compound 44

The analogs of Compound 44 can then be reacted with analogs of Compound16:

Analogs of Compound 16,

(wherein Z², X, and R⁹ are as defined herein) to form analogs ofCompound 46:

It will also be recognized that stereochemical configurations other thanthose shown (i.e., enantiomers or diasteriomers) can be prepared by theselection of analogs of Compound 44 having the appropriatestereochemical configuration at the chiral centers.

Compound 47

Compound 47 is commercially available from TCI.

Compound 48

To a solution of Compound 9 (500 mg, 3 mmol) in CH₂Cl₂ (3 mL) was addedCompound 47 (500 mg, 2.5 mmol). The mixture was stirred for 14 hours.Purification by flash column chromatography (hexanes/EtOAc=1/1.5) gaveCompound 48 (242 mg). m/z: 372.1 (M+H)⁺.

Compound 49

To a solution of Compound 48 (240 mg, 0.65 mmol) in dioxane (4 mL) andwater (4 mL) was added sodium hydroxide (40 mg, 1 mmol). The mixture wasstirred for 1 hour and acidified with 4 N HCl in dioxane (0.25 mL, 1mmol). The mixture was extracted with EtOAc and organic phase was driedwith MgSO₄. Concentration gave Compound 49 (200 mg). m/z: 356.2 (M−H)⁺.

Example O

To a solution of corresponding acid 49 (30 mg, 0.08 mmol) and Compound46 (22 mg, 0.05 mmol) in THF (1 mL) were added HOBt (15 mg, 0.11 mmol),EDC (20 μL, 0.11 mmol), and disopropylethylamine (0.2 mL). The mixturewas stirred for 12 hours and concentrated. Purification by flash columnchromatography (hexanes/EtOAc=1/5 to 0/100) gave Example O (17 mg). m/z:749.3 (M+H)⁺.

Example P

To Example O (17 mg) was added TFA (2 mL). The mixture was stirred for 3hours and concentrated. The mixture was diluted with THF (2 mL) and 1.0N NaOH solution was added until pH 11. The mixture was stirred for 10minutes, and extracted with EtOAc. The organic phase was washed withwater and brine. Purification by flash column chromatography (EtOAc)gave Example P (12 mg). ¹H-NMR (CDCl₃) δ 8.76 (1H, s), 7.79 (1H, s),7.25-6.9 (11H, m), 6.51 (1H, broad), 5.42 (1H, m), 5.18 (2H, m), 4.42(2H, m), 4.22 (1H, m), 4.10 (1H, m), 3.95 (1H, m), 3.79 (1H, m), 3.58(1H, m), 3.23 (1H, m), 2.93 (3H, s), 2.9-2.5 (4H, m), 1.6-1.2 (10H, m);m/z: 693.2 (M+H)⁺.

Preparation of Examples O, R, and S

Compound 50

Compound 50 is commercially available from Chem Impex International, andused without further purification.

Compound 51

Compound 50 (7.0 g, 26.0 mmol) was dissolved in CH₂Cl₂ (330 mL) and1,1-carbonyldiimidazole (4.22 g, 26.0 mmol) was added, followed byi-Pr₂NEt (19 mL, 104 mmol). The solution was stirred at 25° C. for 12hours. Compound 9 (4.44 g, 26.0 mmol) was dissolved in 20 mL of CH₂Cl₂and added to the reaction mixture. The solution was stirred at 25° C.for 7 hours. The solvent was removed in vacuo and the residue wasdiluted with ethyl acetate and washed with water and brine. The organiclayers were dried (Na₂SO₄), filtered, and evaporated. Purification byCombiflash® (stationary phase: silica gel; eluent: 66-100% EtOAc/Hexanegradient) gave Compound 51 (7.34 g). m/z: 429.0 (M+H)⁺.

Compound 52

Compound 51 (7.34 g, 17.13 mmol) was dissolved in THF (90 mL) and 1Maqueous LiOH (35 mL) was added. The mixture was stirred at 25° C. for0.5 hour. The reaction was quenched with 1M HCl (51 mL) and the mixturewas adjusted to pH 2. The mixture was extracted with ethyl acetate. Theorganic layers were dried over Na₂SO₄, filtered, and evaporated toprovide Compound 52 (7.00 g). The recovered Compound 52 was used in thenext step without further purification. m/z: 415.0 (M+H)⁺.

The skilled practitioner will recognize that the procedure outlined inScheme 19 can be used to prepare a variety of compounds analogous toCompounds 51 and 52. For example, amines analogous to Compound 9 can bereacted with the appropriate amino ester analogous to Compound 50:

to form compounds analogous to Compound 51, which are further reacted toform compounds analogous to Compound 52:

wherein R¹, R², R⁷, R¹ and Y are as defined herein.

It will also be recognized that stereochemical configurations other thanthose shown (i.e., enantiomers or diasteriomers) can be prepared by theselection of analogs of Compound 50 having the appropriatestereochemical configuration at the chiral center.

Example Q

Compound 52 (2.57 g, 6.21 mmol) was dissolved in THF (67 mL). Compound 8(2.10 g, 5.13 mmol) was added, followed by HOBt (1.04 g, 7.70 mmol),i-Pr₂NEt (3.67 mL, 20.52 mmol), and EDC (1.82 mL, 10.26 mmol). Themixture was stirred at 25° C. for 12 hours. The solvent was removedunder reduced pressure. The residue was diluted with ethyl acetate andwashed sequentially with saturated aqueous Na₂CO₃, water, and brine. Theorganic phase was dried over Na₂SO₄, filtered, and evaporated.Purification by flash column chromatography (stationary phase: silicagel; eluent: 5% iPrOH/CH₂Cl₂) gave Example Q (3.02 g). m/z: 806.2(M+H)⁺.

Example R

Example Q (3.02 g, 3.74 mmol) was suspended in 4.0 N HCl/dioxanesolution (30 mL) and stirred at 25° C. for 3 hours. Solvent was removedunder reduced pressure and Et₂O was poured into the reaction mixture.The resulting suspension was stirred vigorously for 1.5 hours. The solidwas allowed to settle and the ether layer was decanted. Washing of theprecipitate with Et₂O was repeated two more times. The product was driedin vacuo to afford a white solid (3.18 g, quantitative yield). Saturatedaqueous Na₂CO₃ solution was added to above solid (3.18 g) with stirringuntil solid disappeared. The aqueous solution was extracted with ethylacetate. The organic phases were dried over Na₂SO₄, filtered, andevaporated to afford Example R as a yellow foam (2.44 g, 81%). Therecovered Example R was used without further purification in the nextstep. m/z: 706.1 (M+H)⁺.

Example S Method I

Example R (1.00 g, 1.42 mmol) was dissolved in DMF (20 mL) andbromoethyl ether (196 μL, 1.56 mmol) was added dropwise, followed byNaHCO₃ (0.239 g, 2.84 mmol). The reaction mixture was stirred at 25° C.for 2 hours. The solution was heated to 65° C. and stirred for 12 hours.The solvent was removed under reduced pressure. The residue was dilutedwith EtOAc and washed sequentially with water and brine. The organicphase was dried over Na₂SO₄ filtered, and evaporated. Purification byreverse-phase HPLC (Phenomenex Synergi® Comb-HTS column, eluent: 5-95%CH₃CN/water) gave Compound 70 (580 mg, 53%). ¹H NMR (CDCl₃) δ 8.98 (s,1H); 7.90 (s, 1H); 7.75 (m, 1H); 7.40-7.00 (m, 11H), 6.55 (br s, 1H);5.58 (m, 1H); 5.28, 5.19 (d_(AB), J=14 Hz, 2H); 4.70-4.37 (m, 3H); 3.99(m, 5H); 3.76 (br s, 1H); 3.65-3.30 (m, 3H); 2.97 (m, 5H); 2.90-2.60 (m,6H); 2.28 (br s, 1H); 1.91 (br s, 1H); 1.60-1.30 (m, 10H). m/z: 776.2(M+H)⁺

Method II

Compound 54

Compound 54 was prepared following the procedure described in J. Med.Chem. 1993, 36, 1384 (herein incorporated by reference in its entiretyfor all purposes).

To solution of Compound 53 (0.550 g, 5.28 mmol) (Sigma-Aldrich) in H₂O(8.8 mL) at 0° C. was added NaIO₄ (1.016 g, 4.75 mmol). The mixture wasallowed to slowly warm to 25° C. and stirred for 12 hours. Solid NaHCO₃was added to the reaction mixture until pH 7. CHCl₃ (16 mL) was addedand the mixture was allowed to stir for 5 minutes. The mixture wasfiltered and the solid was washed with CHCl₃ (6 mL). The combinedH₂O/CHCl₃ solution was used directly in the next step without furtherpurification.

Example S

To a solution of Example R (70 mg, 0.1 mmol) in CH₃CN (5 mL) was addedsodium cyanoborohydride (50 mg) in water (5 mL). To the above mixturewas added a solution of dialdehyde Compound 54 (0.6 mmol) in CHCl₃/H₂O)(4 mL/1 mL). The mixture was stirred for 12 hours, and basified withsaturated Na₂CO₃ solution. The mixture was extracted with EtOAc, andorganic phase was washed with water and brine, and dried over Na₂SO₄.Purification by reverse-phase HPLC (Phenomenex Synergi® Comb-HTS column)gave Example S (57 mg).

Method III

Compound 55

Compound 51 (0.28 g, 0.66 mmol) was dissolved in CH₂Cl₂ (4 mL) and TFA(1 mL) was added dropwise. The reaction was allowed to stir at 25° C.for 1 hour. The solvent was removed under reduced pressure to affordCompound 55 (0.39 g). m/z: 329.0 (M+H)⁺.

Compound 56

To a solution of Compound 55 (0.39 g, 0.89 mmol) in CH₃CN (45 mL) wasadded NaBH₃CN (0.45 g, 7.12 mmol) and H₂O (45 mL). A solution ofCompound 54 (0.55 g, 5.34 mmol) in CHCl₃/H₂O (40 mL) was added. Themixture was stirred at 25° C. for 12 hours. The reaction mixture wasmade basic with saturated aqueous Na₂CO₃ and extracted sequentially withethyl acetate and dichloromethane. The combined organic layers werewashed sequentially with H₂O and brine, dried over Na₂SO₄, filtered, andevaporated. Purification by Combiflash® (stationary phase: silica gel;eluent: 0-10% MeOH/CH₂Cl₂ gradient) gave Compound 56 (0.17 g). m/z:399.1 (M+H)⁺.

Compound 57

Compound 56 (377 mg, 0.95 mmol) was dissolved in THF (4 mL) and 1Maqueous LiOH (1.90 mL) was added. The mixture was stirred at 25° C. for1 hour. The reaction was neutralized with 1M HCl. THF was removed underreduced pressure and the aqueous solution was lyophilized to affordCompound 57 (365 mg). The material was used directly in the next stepwithout further purification. m/z: 385.1 (M+H)⁺.

Example S

Example S (185 mg, 57%) was prepared following the same procedure as forExample Q, except that Compound 57 (160 mg, 0.42 mmol) was used insteadof Compound 52. mass m/z: 776.2 (M+H)⁺.

The skilled practitioner will recognize that the procedure outlined inScheme 22 can be used to prepare a variety of compounds analogous toCompounds 55-57:

in R⁷, R⁸ and Y are as defined herein.

It will also be recognized that stereochemical configurations other thanthose shown (i.e., enantiomers or diasteriomers) can be prepared by theselection of analogs of Compound 51 having the appropriatestereochemical configuration at the chiral center.

Method IV

Compound 59

To a solution of Compound 122 (33 g, 112 mmol) (see Scheme 69) inethanol (366 mL) at 0° C. was added a solution of sodium hydroxide (4.7g, 117 mmol) in water (62 mL). The mixture was stirred for one hour at25° C. and solvents were removed under reduced pressure. The mixture wascoevaporated with ethanol (3×400 mL), and dried at 60° C. for two hoursunder high vacuum to give a white solid. To the solution of above solidin DMF (180 mL) was added benzyl bromide (16.2 mL, 136 mmol). Themixture was stirred for 16 hours under darkness, and was quenched withwater (300 mL). The mixture was extracted with EtOAc (4×300 mL). Thecombined organic phase was washed with water (5×) and brine, and driedover Na₂SO₄. Concentration gave Compound 59 (48 g), which was used inthe next step without further purification.

Compound 60

A mixture of Compound 59 (33 g, 74 mmol) in DMSO (225 mL) and Et₃N (36mL) was stirred for 30 minutes. The mixture was cooled to 0-10° C.SO₃-pyridine (45 g) was added, and the stirring was continued for 60minutes. Ice (300 g) was added, and the mixture was stirred for 30minutes. EtOAc (300 mL) was added and sat. Na₂CO₃ was added until pH was9-10. The organic phase was separated from the aqueous phase, and theaqueous phase was extracted with EtOAc (2×300 ml). The combined organicphases were washed with sat Na₂CO₃ (2×), water (3×), and brine. Themixture was dried over Na₂SO₄ and concentrated to give Compound 60 (32g), which was used directly in next step without further purification.

Compound 61

To a solution of Compound 60 (32 g) in CH₃CN (325 mL) was addedmorpholine (12.9 mL, 148 mmol), with a water bath around the reactionvessel, followed by HOAc (8.9 mL, 148 mmol), and NaBH(OAc)₃ (47 g, 222mmol). The mixture was stirred for 12 hours. CH₃CN was removed underreduced pressure, and the mixture was diluted with EtOAc (300 mL). Sat.Na₂CO₃ was added until the pH was 9˜10. The organic phase was separatedfrom the aqueous phase, and the aqueous phase was extracted with EtOAc(2×300 mL). The combined organic phases were washed with sat Na₂CO₃(2×), water (1×), and brine (1×). The mixture was dried over Na₂SO₄. Theresulting residue was concentrated and purified by silica gel columnchromatography (EtOAc to DCM/iPrOH=10/1) to give Compound 61 (30 g).

Compound 57

To a solution of Compound 61 (26.5 g, 56 mmol) in ethanol (160 mL) at 0°C. was added a solution of sodium hydroxide (2.5 g, 62 mmol) in water(30 mL). The mixture was stirred for one hour at 25° C., and solventswere removed under reduced pressure. The mixture was diluted with water(200 mL), and was washed with CH₂Cl₂ (6×100 mL). The water phase wasacidified with 12 N HCl (5.2 mL), and was dried under reduced pressureto give Compound 57 (22 g).

Example S

Compound 57 was converted to Example S using the procedure described inMethod III, above.

Preparation of Compounds T and U

Example T Method I

The hydrochloride salt of Example R (100 mg, 0.13 mmol) was suspended inCH₂Cl₂ (2 mL) and dissolved by addition of iPr₂NEt (69 μL). Acetylchloride (11 μL) was added dropwise and the mixture was allowed to stirat 25° C. for 4 hours. The solvent was removed in vacuo. Purification ofthe residue by flash column chromatography (stationary phase: silicagel; eluent: 8% iPrOH/CH₂Cl₂) gave Example T (39 mg, 40%). m/z: 748.2(M+H)⁺. ¹H NMR (CDCl₃) δ 8.85 (s, 1H); 7.87 (s, 1H); 7.73 (s, 1H);7.40-7.00 (m, 13H); 6.45 (br s, 1H); 5.70 (m, 1H); 5.32, 5.22 (d_(AB),J=13 Hz, 2H); 4.51 (s, 2H); 4.20-3.90 (m, 4H); 3.78 (m, 1H); 3.38 (m,2H); 3.20-2.50 (m, 8H); 1.95 (s, 4H); 1.82 (m, 2H); 1.41 (m, 6H).

Method II

Saturated aqueous Na₂CO₃ solution was added to the hydrochloride salt ofExample R (3.18 g, 3.46 mmol) while stirring until the soliddisappeared. The aqueous solution was extracted with ethyl acetate. Theorganic phases were dried over Na₂SO₄, filtered, and evaporated toafford Example R as a yellow foam (2.44 g, 81%). This material was usedwithout further purification in the next step. m/z: 706.1 (M+H)⁺.

Example R (300 mg, 0.43 mmol) was dissolved in THF (5.5 mL). Acetic acid(37 μL, 0.64 mmol) was added, followed by HOBt (85 mg, 0.64 mmol),iPr₂NEt (304 μL, 1.70 mmol), and EDC (151 μL, 0.85 mmol). The reactionmixture was allowed to stir at 25° C. for 12 hours. The solvent wasremoved under reduced pressure. The residue was diluted with EtOAc andwashed sequentially with saturated aqueous Na₂CO₃, water, and brine. Theorganic phase was dried over Na₂SO₄, filtered, and evaporated.Purification by Combiflash® (stationary phase: silica gel; eluent: 10%MeOH/CH₂Cl₂) gave Example T (249 mg, 77%). m/z: 748.2 (M+H)⁺.

Example U

Example R (100 mg, 0.13 mmol) was suspended in CH₂Cl₂ (2 mL) anddissolved by addition of iPr₂NEt (69 μL). Methanesulfonyl chloride (12μL) was added dropwise and the mixture was allowed to stir at 25° C. for4 hours. The solvent was removed in vacuo. Purification of the residueby flash column chromatography (stationary phase: silica gel; eluent: 8%iPrOH/CH₂Cl₂) gave Example U (55 mg, 54%). m/z: 784.2 (M+H)⁺. ¹H NMR(CDCl₃) δ 8.90 (s, 1H); 7.88 (s, 1H); 7.40-7.00 (m, 12H); 6.54 (br s,1H); 6.19 (br s, 1H); 5.25 (s, 2H); 4.53 (s, 2H); 4.38 (m, 1H); 4.12 (m,1H); 3.79 (m, 1H); 3.79 (m, 1H); 3.48 (m, 1H); 2.99 (s, 3H); 2.90 (m,3H); 2.73 (m, 6H); 2.00 (m, 1H); 1.79 (m, 1H); 1.60-1.18 (m, 10H).

Preparation of Examples V, W, X and Y

Example V

Example V (692 mg) was prepared following the same procedure used forpreparing Example Q, except that Compound 46 was used instead ofCompound 8. m/z: 806.2 (M+H)⁺.

Example W

Example W (770 mg, quantitative yield) was prepared following the sameprocedure for Example R except that Example V was used instead ofExample Q. m/z: 706.2 (M+H)⁺. ¹H NMR (CD₃OD) δ 9.86 (s, 1H); 8.23 (s,1H); 7.66 (s, 1H); 7.40-7.00 (m, 10H); 5.29, 5.17 (d_(AB), J=13 Hz, 2H);4.80-4.60 (m, 2H); 4.18 (s, 2H); 4.26 (m, 2H); 3.67 (br s, 1H); 3.55 (m,2H); 3.03 (m, 3H); 2.90-2.60 (m, 8H); 2.53 (s, 2H); 2.00-1.80 (m, 2H);1.85-1.30 (m, 10H).

Compound 59 Method I

Example X (107 mg, 55%) was prepared following the Method I procedurefor Example T except that Example W was used instead of Example R. m/z:748.2 (M+H)⁺. ¹H NMR (CDCl₃) δ 8.80 (s, 1H); 7.85 (s, 1H); 7.40 (m, 1H);7.38-7.00 (m, 10H), 6.94 (s, 1H); 6.30 (m, 2H); 5.75 (m, 1H); 5.30, 5.23(d_(AB), J=13 Hz, 2H); 4.54, 4.46 (d_(AB), J=8 Hz, 2H); 4.20-3.90 (m,2H); 3.74 (br s, 1H); 3.46 (br s, 1H); 3.28 (m, 1H); 2.98 (s, 3H); 2.83(m, 3H); 2.72 (m, 1H); 2.62 (m, 1H); 2.05-1.20 (m, 15H).

Method II

Example X (205 mg, 65%) was prepared following the Method II procedurefor Example T except that Example W was used instead of Example R. m/z:748.2 (M+H)⁺.

Example Y

Example Y (106 mg, 50%) was prepared following the same procedure forExample U, except that Example W was used instead of Example R. m/z:784.2 (M+H)⁺. ¹H NMR (CDCl₃) δ 8.81 (s, 1H); 7.85 (s, 1H); 7.40-7.05 (m,10H), 6.98 (s, 1H); 6.22 (br s, 1H); 5.78 (s, 1H); 5.25 (m, 4H); 4.29(m, 2H); 4.33 (br s, 1H); 4.12 (br s, 1H); 3.77 (br s, 1H); 3.10 (br s,1H); 2.98 (s, 3H); 2.90 (s, 3H); 2.73 (m, 6H); 2.00-1.20 (m, 12H).

Preparation of Examples Z-AD

Compound 62

Tert-butyl 2-aminoethylcarbamate (62) is commercially available fromAldrich, and was used without further purification.

Compound 63

To a solution of Compound 62 (2.0 mmol) in CH₃CN (15 mL) was addedCompound 16 (1.82 mmol), followed by the addition ofN,N-diisopropylethylamine (0.61 mL). The mixture was stirred at 25° C.for 12 hours. The solvent was removed in vacuo, and the residue wasdiluted with ethyl acetate and washed sequentially with saturatedaqueous Na₂CO₃, water, and brine. The organic layers were dried withNa₂SO₄, filtered, and evaporated. Purification by Combiflash®(stationary phase: silica gel; eluent: 25-100% EtOAc/hexane gradient)gave Compound 63. m/z: 301.9 (M+H)⁺.

Compound 64

To a solution of Compound 63 (1.05 mmol) in EtOAc (3 mL) was added 4NHCl/dioxane solution (1.1 mL). The mixture was allowed to stir at 25° C.for 12 hours. The solvent was removed under reduced pressure, andCompound 64 was obtained as a white powder. This material was used inthe next step without further purification. m/z: 216.0 (M+H)⁺.

Example Z

Compound 64 (70 mg, 0.29 mmol) was dissolved in THF (2.2 mL). Compound29 (91 mg, 0.29 mmol) was added to the reaction flask as a 1.0M solutionin THF, followed by HOBt (59 mg, 0.44 mmol), N,N-diisopropylethylamine(207 μL, 1.16 mmol), and EDC (103 μL, 0.58 mmol). The reaction wasallowed to stir for 12 hours at 25° C. and concentrated under reducedpressure. The residue was diluted with EtOAc and washed sequentiallywith saturated aqueous Na₂CO₃, water, and brine. The organic layers weredried with Na₂SO₄, filtered, and evaporated. Purification by Combiflash®(stationary phase: silica gel; eluent: 0-10% MeOH/CH₂Cl₂ gradient) gaveExample Z (54 mg, 38%). m/z: 497.1 (M+H)⁺. ¹H NMR (CDCl₃) δ 8.78 (s,1H); 7.83 (s, 1H); 6.99 (s, 1H); 6.80 (br s, 1H); 6.22 (br s, 1H); 5.87(br s, 1H); 5.25 (s, 2H); 4.43 (s, 2H); 3.97 (m, 1H); 3.34 (m, 4H); 2.95(s, 3H); 2.22 (m, 2H); 1.38 (d, J=7 Hz, 6H); 0.97 (d, J=7 Hz, 6H).

Example AA

Example AA was prepared following the procedures for steps I-III (Scheme20) for Example Z, with the exception that tert-butyl3-aminopropylcarbamate was used instead of tert-butyl2-aminoethylcarbamate (Compound 62). After Combiflash® purification, 38mg (34%) of Example AA was obtained. m/z: 511.1 (M+H)⁺. ¹H NMR (CDCl₃) δ8.78 (s, 1H); 7.84 (s, 1H); 6.96 (s, 2H); 6.17 (br s, 1H); 5.80 (m, 1H);5.26 (m, 2H); 4.44 (s, 2H); 4.09 (m, 1H); 3.40-3.10 (m, 5H); 2.97 (s,3H); 2.20 (m, 1H); 1.60 (m, 2H); 1.36 (d, J=7 Hz, 6H); 0.96 (d, J=7 Hz,6H).

Example AB

Example AB was prepared following the procedures for steps I-III (Scheme20) for Example Z, with the exception that tert-butyl1-piperazinecarboxylate was used instead of tert-butyl2-aminoethylcarbamate (Compound 62). After Combiflash® purification, 64mg (45%) of Example AB was obtained. m/z: 523.1 (M+H)⁺. ¹H NMR (CDCl₃) δ8.82 (s, 1H); 7.89 (s, 1H); 6.96 (s, 1H); 5.93 (br s, 1H); 5.35 (s, 2H);4.62 (m, 1H); 4.50 (m, 2H); 3.80-3.40 (m, 8H); 3.34 (m, 1H); 3.00 (s,3H); 1.97 (m, 1H); 1.40 (d, J=7 Hz, 6H); 0.96, 0.93 (d, J=7 Hz, 6H).

Example AC

Example AC was prepared following the procedures for steps I-III (Scheme20) for Example Z, with the exception that tert-butyl4-amino-1-piperidinecarboxylate was used instead of tert-butyl2-aminoethylcarbamate (Compound 62). After Combiflash® purification, 60mg (44%) of Example AC was obtained. m/z: 537.1 (M+H)⁺. ¹H NMR (CDCl₃) δ8.82 (s, 1H); 7.87 (s, 1H); 6.97 (s, 1H); 5.82 (br s, 1H); 5.30 (m, 3H);4.80-4.40 (m, 5H); 4.03 (m, 1H); 3.72 (br s, 1H); 3.34 (m, 1H); 3.18 (m,1H); 3.01 (s, 3H); 2.79 (m, 1H); 2.20-1.90 (m, 4H); 1.40 (d, J=7 Hz,6H); 0.97, 0.90 (d, J=7 Hz, 6H).

Example AD

Example AD was prepared following the procedures I-III for Example Z,with the exception that tert-butyl 4-piperidinylcarbamate was usedinstead of tert-butyl 2-aminoethylcarbamate (Compound 62). AfterCombiflash® purification, 49 mg (36%) of Example AD was obtained. m/z:537.1 (M+H)⁺. ¹H NMR (CDCl₃) δ 8.82 (s, 1H); 7.87 (s, 1H); 7.01 (s, 1H);6.33 (br s, 1H); 6.11 (br s, 1H); 5.32 (s, 2H); 4.47 (s, 2H); 4.20-3.80(m, 4H); 3.35 (m, 1H); 3.10-2.80 (m, 6H); 2.21 (m, 2H); 1.90 (m, 2H);1.40 (d, J=7 Hz, 6H); 0.97 (d, J=7 Hz, 6H).

Preparation of Examples AE-AG

Compound 65

Compound 65 is commercially available from Chem Impex International, andwas used without further purification.

Compound 66

Compound 65 (956 mg, 4.0 mmol) was dissolved in CH₂Cl₂ (45 mL) and1,1-carbonyldiimidiazole (648 mg, 4.0 mmol) was added, followed byi-Pr₂NEt (2.8 mL, 16 mmol). The solution was stirred at 25° C. for 12hours. Compound 9 (679 mg, 4.0 mmol) was dissolved in CH₂Cl₂ (5 mL) andadded to the reaction. The mixture was allowed to stir for 5 hours.Then, the solvent was removed under reduced pressure. The residue wasdiluted with ethyl acetate and filtered through celite. The ethylacetate was then removed in vacuo. Purification by flash columnchromatography (stationary phase: silica gel; eluent: EtOAc) gaveCompound 66 (841 mg). m/z: 400.0 (M+H)⁺.

Compound 67

Compound 66 (841 mg, 2.11 mmol) was dissolved in THF (9 mL) and 2Naqueous NaOH was added. The solution was stirred at 25° C. for 2 hours.The reaction was adjusted to pH 2 with 1N HCl. The mixture was extractedwith ethyl acetate, dried over Na₂SO₄, filtered, and evaporated.Compound 67 (772 mg) was used directly in the next step without furtherpurification. m/z: 386.0 (M+H)⁺.

Example AE

Compound 67 (569 mg, 1.48 mmol) was dissolved in THF (17 mL). Compound 8(970 mg, 2.37 mmol) was added, followed by HOBt (300 mg, 2.22 mmol),i-Pr₂NEt (1.06 mL, 5.92 mmol), and EDC (0.52 mL, 2.96 mmol). The mixturewas stirred at 25° C. for 36 hours. The solvent was removed underreduced pressure. The resulting residue was diluted with ethyl acetateand washed sequentially with saturated aqueous Na₂CO₃, water, and brine.The organic phase was dried over Na₂SO₄, filtered, and evaporated.Purification by flash column chromatography (stationary phase: silicagel; eluent: 8% iPrOH/CH₂Cl₂) gave Example AE (3.02 g). m/z: 777.2(M+H)⁺.

Example AF

Example AE (100 mg, 0.13 mmol) was dissolved in neat TFA (3 mL). Themixture was stirred at 25° C. for 2 hours. The solvent was removed underreduced pressure. Purification by reverse-phase HPLC (PhenomenexSynergi® Comb-HTS column, eluent: 5-95% CH₃CN/H₂O gradient) gave ExampleAF (20 mg, 21%). m/z: 721.2 (M+H)⁺. ¹H NMR (CDCl₃) δ 8.92 (s, 1H); 7.91(s, 1H); 7.40-7.00 (m, 11H); 6.41 (br s, 1H); 6.12 (br s, 1H); 5.40-5.00(m, 3H); 4.70-4.50 (m, 3H); 4.05 (br s, 1H); 3.81 (br s, 1H); 3.51 (brs, 1H); 2.97 (s, 3H); 2.90-2.60 (m, 6H); 1.41 (d, J=7 Hz, 10H).

Example AG

Example AF (70 mg, 0.10 mmol) was dissolved in dioxane (0.5 mL). DMF (83μL), pyridine (25 μL, 0.29 mmol), di-tert-butyldicarbonate (27 mg, 0.13mmol), and ammonium bicarbonate (15 mg, 0.19 mmol) were added. Themixture was stirred at 25° C. for 48 hours, then diluted with ethylacetate and washed sequentially with water and brine. The organic phasewas dried over Na₂SO₄, filtered, and evaporated. Purification byreverse-phase HPLC (Phenomenex Synergi® Comb-HTS column, eluent: 5-95%CH₃CN/H₂O gradient) gave Example AG (35 mg, 50%). ¹H NMR (CDCl₃) δ 8.80(s, 1H); 7.84 (s, 1H); 7.40-7.00 (m, 10H); 7.08 (s, 1H); 6.83 (m, 1H);6.65 (m, 1H); 5.40-5.10 (m, 4H); 4.60-4.40 (m, 3H); 4.06 (m, 1H); 3.79(m, 1H); 3.36 (m, 1H); 2.97 (s, 3H); 2.90-2.60 (m, 6H); 2.45 (m, 1H);1.70-1.20 (m, 10H).

Preparation of Compounds 68 and 69

Compound 15

Compound 15 is commercially available from Molekula, and was usedwithout further purification.

Compound 68

Compound 15 (6.81 g, 59.1 mmol) was dissolved in CH₃CN (340 mL) andmethanesulfonyl chloride (7.03 mL, 65.1 mmol) was added, followed bytriethylamine (9.03 mL, 65.1 mmol). After the mixture was stirred for 20min, 40% wt. methylamine/water (516 mL) was added to the reactionmixture. The solution was stirred for 12 hours at 25° C. Solvent wasremoved under reduced pressure and the residue was partitioned betweensaturated aqueous Na₂CO₃ and CH₂Cl₂. The organic phase was separated,dried over Na₂SO₄, filtered, and evaporated. Purification by flashchromatography (stationary phase: silica gel; eluent: 0-10% MeOH/CH₂Cl₂gradient) gave Compound 68 (5.07 g). m/z: 128.9 (M+H)⁺.

Compound 69

Compound 15 (10.0 g, 80 mmol) was dissolved in CH₃CN (500 mL) andmethanesulfonyl chloride (7.0 mL, 88 mmol) was added, followed bytriethylamine (12.3 mL, 88 mmol). After the mixture was stirred for 2 h,cyclopropylamine (140 mL, 2000 mmol) in CH₃CN (500 mL) was added to thereaction mixture. The solution was stirred for 36 hours at 25° C.Solvent was removed under reduced pressure and the slurry waspartitioned between saturated aqueous Na₂CO₃ and 3:1 CH₂Cl₂:i-PrOH. Theorganic phase was separated, dried over Na₂SO₄, filtered, andevaporated. Compound 69 (12.81 g) was used in the next step withoutfurther purification. m/z: 155.0 (M+H)⁺.

Preparation of Examples AH and AI

Compound 70

Compound 68 (1.00 g, 7.80 mmol) was dissolved in THF (25 mL) andCompound 10e (2.51 g, 7.09 mmol) was added, followed byN,N-dimethaminopyridine (200 mg, 1.63 mmol), and triethylamine (4.34 mL,31.2 mmol). The mixture was allowed to stir at 60° C. for 6 hours.Solvent was removed under reduced pressure. The residue was diluted withethyl acetate and washed sequentially with saturated aqueous Na₂CO₃,H₂O, and brine. The organic layer was dried over Na₂SO₄, filtered, andevaporated. The resulting residue was purified by Combiflash®(stationary phase: silica gel; eluent: 20-100% EtOAc/Hexane gradient) togive Compound 70 (2.14 g). m/z: 343.9 (M+H)⁺.

Compound 71

Compound 70 (2.14 g, 6.23 mmol) was dissolved in THF (25 mL) and 1Maqueous LiOH (12.5 mL) was added. The mixture was stirred at 25° C. for2 hours. The reaction was quenched with 1M HCl (15 mL) and the mixturewas adjusted to pH 2. The mixture was extracted with ethyl acetate. Theorganic layers were dried over Na₂SO₄, filtered, and evaporated toprovide Compound 71 (1.96 g). This material was used in the next stepwithout further purification. m/z: 330.0 (M+H)⁺.

Example AH

Compound 71 (43 mg, 0.13 mmol) was dissolved in THF (1.5 mL). Compound 8(50 mg, 0.12 mmol) was added, followed by HOBt (24 mg, 0.18 mmol),iPr₂NEt (86 μL, 0.48 mmol), and EDC (42 μL, 0.24 mmol). The mixture wasstirred at 25° C. for 12 hours. The solvent was removed under reducedpressure, and the resulting residue was diluted with ethyl acetate andwashed sequentially with saturated aqueous Na₂CO₃, water, and brine. Theorganic phase was dried over Na₂SO₄, filtered, and evaporated.Purification by flash column chromatography (stationary phase: silicagel; eluent: 1-10% MeOH/CH₂Cl₂ gradient) gave Example AH (66 mg). m/z:721.2 (M+H)⁺.

Compound AI

Example AH (66 mg, 0.09 mmol) was dissolved in TFA and allowed to stirat 25° C. for 3 hours. The solvent was removed under reduced pressureand the residue was diluted with THF (3 mL) and 2N aqueous NaOH wasadded until pH 12. The mixture was allowed to stir for 20 min andextracted with EtOAc. The organic layer was washed sequentially withwater and brine, dried over Na₂SO₄, filtered, and evaporated.Purification by flash chromatography (stationary phase: silica gel;eluent: 0-20% i-PrOH/CH₂Cl₂ gradient) gave Example AI (71 mg, 97%). m/z:665.2 (M+H)⁺. ¹H NMR (CDCl₃) δ 8.84 (s, 1H); 8.80 (s, 1H); 7.85 (s, 1H);7.79 (s, 1H); 7.40-7.00 (m, 10H); 6.69 (m, 1H); 5.34 (m, 1H); 5.24 (s,2H); 4.86 (m, 2H); 4.73, 4.59 (d_(AB), J=16 Hz, 2H); 4.30 (s, 1H); 4.15(m, 2H); 3.86 (br s, 1H); 2.88 (s, 3H); 2.85-2.60 (m, 4H); 2.01 (s, 1H);1.58 (s, 2H); 1.44 (s, 2H); 1.09 (d, J=56 Hz, 3H).

Preparation of Examples AJ and AK

Compound 47

Compound 47 is commercially available from TCI America, and was usedwithout further purification.

Compound 72

Compound 72 was prepared following procedure for Compound 48 (MethodII), except that Compound 68 was used instead of Compound 9.

Compound 73

Compound 73 was prepared following procedure for Compound 49, exceptthat Compound 72 was used instead of Compound 48.

Example AJ

Example AJ (70 mg) was prepared following the same procedure used toprepare Example AH, with the exception that Compound 73 (41 mg, 0.13mmol) was used instead of Compound 71. m/z: 707.2 (M+H)⁺.

Example AK

Example AK (43 mg, 67%) was prepared following the same procedure usedto prepare Example AI, with the exception that Example AJ (70 g, 0.10mmol) was used instead of Example AH. m/z: 651.2 (M+H)⁺. ¹H NMR (CDCl₃)δ 8.83 (s, 2H); 7.84 (s, 1H); 7.79 (s, 1H); 7.40-7.00 (m, 10H); 6.65 (brs, 1H); 5.47 (br s, 1H); 5.24 (s, 2H); 4.90 (m, 1H); 4.82-4.50 (m, 2H);4.30-4.00 (m, 3H); 3.84 (br s, 1H); 3.49 (m, 1H); 2.87 (s, 3H); 2.75 (brs, 5H); 1.60-1.20 (m, 4H).

Preparation of Examples AL and AM

Compound 74

Compound 69 (1.56 g, 10.1 mmol) was dissolved in CH₂Cl₂ (10 mL).Compound 47 (1.7 g, 8.5 mmol) in CH₂Cl₂ (20 mL) was added, followed byiPr₂NEt (3.02 mL, 16.9 mmol). The reaction was stirred at 25° C. for 12hours. The solvent was removed under reduced pressure. The residue wasdiluted with ethyl acetate and washed sequentially with water and brine,dried over Na₂SO₄, filtered, and evaporated. Purification by Combiflash®(stationary phase: silica gel; eluent: 50-100% EtOAc/hexane gradient)gave Compound 74 (2.92 g). m/z: 356.0 (M+H)⁺.

Compound 75

Compound 74 (0.97 mmol) was taken up in THF (3 mL) and treated withfreshly prepared 1M LiOH (2 mmol) and stirred vigorously for 1 h. Thereaction was quenched with 1M HCl (2.5 mmol) and extracted with EtOAc(3×15 mL). The combined organics were washed with brine (25 mL), driedover anhydrous Na₂SO₄ and concentrated in vacuo to produce 0.331 g(quant) of Compound 75 as a colorless film (m/z 342.0 (M+H)⁺).

Example AL

Example AL (2.20 g) was prepared following the same procedure used toprepare Example AH, with the exception that Compound 75 (2.00 g, 4.88mmol) was used instead of Compound 71. m/z: 733.2 (M+H)⁺.

Example AM

Example AM (1.88 g, 92%) was prepared following the same procedure usedto prepare Example AI, with the exception that Example AL (2.20 g, 3.01mmol) was used instead of Example AH. m/z: 677.2 (M+H)⁺. ¹H NMR (CDCl₃)δ 8.79 (s, 1H); 8.72 (s, 1H); 7.82 (s, 1H); 7.77 (s, 1H); 7.40-7.00 (m,10H); 6.59 (m, 1H); 6.31 (m, 1H); 5.23 (s, 2H); 5.00 (m, 1H); 4.72, 4.60(d_(AB), J=15 Hz, 2H); 4.18 (s, 2H); 4.03 (m, 1H); 3.84 (br s, 1H); 3.48(m, 1H); 2.85-2.60 (m, 4H); 2.37 (br s, 2H); 1.58 (s, 2H); 1.41 (s, 2H);0.93 (m, 2H); 0.76 (m, 2H).

Compound 76

Compound 76 (m/z 117.0 (M+H)⁺ of diamine) was prepared using a proceduresimilar to that used to prepare Compound 25 (described in Scheme 7)except that CBZ-L-alininol was used instead of CBZ-D-phenylalininol andStep III was performed with 1 M HCl added.

Compound 77

Compound 77 (m/z 145.0 (M+H)⁺ of diamine) was prepared using a proceduresimilar to that used to prepare Compound 76 except that(S)-(+)-2-CBZ-amino-1-butanol was used instead of CBZ-D-phenylalininol.

Compound 78

Compound 76 (7.93 mmol) is added to a solution of NaOH (16.7 mmol) inH₂O (5 mL) that is cooled to 0° C. and diluted with MeCN (40 mL). DIPEAis added (2.1 mL, 11.9 mmol). Compound 16 (7.9 mmol) is taken up in MeCN(40 mL) and added to the reaction solution dropwise via an additionfunnel over 1 h. The resulting solution is allowed to warm to roomtemperature overnight. The solvent is removed in vacuo and the residuetaken up in 3/1 CHCl₃/IPA (50 mL). The resulting solution is washed withsat. Na₂CO₃ (50 mL) and water is added until the aqueous layer ishomogeneous. The aqueous layer is extracted with 3/1 CHCl₃/IPA (3×25mL). The combined organics are washed with saturated Na₂CO₃ (50 mL),water (50 mL) and brine (50 mL) and are dried over anhydrous Na₂SO₄. Thesolvent is removed in vacuo and the residue purified by columnchromatography on SiO₂ (100% EtOAc, then 0 to 20% MeOH/DCM) to produce0.63 g (31%) of 78 as an off-white solid. (m/z 258.0 (M+H)⁺).

Compound 79

Compound 79 (m/z 286.1 (M+H)⁺) was prepared following the procedure forCompound 78 except that Compound 77 was used instead of Compound 76.

Example AN

Example AN (68 mg) was prepared following the same procedure used toprepare Example AH, with the exceptions that Compound 49 (68 mg, 0.19mmol) was used instead of Compound 71, and Compound 79 (50 mg, 0.18mmol) was used instead of Compound 8. m/z: 625.2 (M+H)⁺.

Example AO

Example AO (66 mg, 76%) was prepared following the same procedure usedto prepare Example AI, with the exception that Example AN (43 mg, 0.13mmol) was used instead of Example AH. m/z: 569.2 (M+H)⁺. ¹H NMR (CDCl₃)δ 8.85 (s, 1H); 7.89 (s, 1H); 7.08 (s, 1H); 6.81 (m, 1H); 5.29 (s, 2H);4.87 (m, 1H); 4.63, 4.48 (d_(AB), J=16 Hz, 2H); 4.31 (m, 1H); 4.11 (m,1H); 3.76 (m, 2H); 3.44 (m, 2H); 3.02 (m, 4H); 1.60-1.20 (m, 14H);1.00-0.70 (m, 6H).

Preparation of Examples AP and AQ

Compound 13d

Compound 13e (1.39 g) was prepared following the same procedure used toprepare Compound 71, with the exception that Compound 12e (1.53 g, 3.97mmol) was used instead of Compound 70 m/z: 372.0 (M+H)⁺.

Example AP

Example AP (87 mg) was prepared following the same procedure used toprepare Example AH, with the exception that Compound 13e (71 mg, 0.19mmol) was used instead of Compound 71, and Compound 79 (50 mg, 0.18mmol) was used instead of Compound 8. m/z: 639.2 (M+H)⁺.

Compound AO

Example AQ (61 mg, 76%) was prepared following the same procedure usedto prepare Example AI, with the exception that Example AP (87 mg, 0.14mmol) was used instead of Example AH. m/z: 583.2 (M+H)⁺. ¹H NMR (CDCl₃)δ 8.81 (s, 1H); 7.87 (s, 1H); 7.01 (s, 1H); 6.87 (m, 1H); 6.52 (s, 1H);5.28 (m, 2H); 4.47 (m, 1H); 4.59, 4.43 (d_(AB), J=16 Hz, 2H); 4.45 (m,1H); 4.17 (br s, 1H); 3.75 (br s, 1H); 3.52 (br s, 1H); 3.35 (br s, 1H);3.01 (m, 3H); 2.07 (br s, 1H); 1.60-1.10 (m, 17H); 1.00-0.70 (m, 6H).

Preparation of Example AR

Compound 80

Compound 80 is commercially available from Chem Impex International, andwas used without further purification.

Compound 81

Compound 80 (2.0 g, 11.0 mmol) was dissolved in CH₂Cl₂ (170 mL) and1,1-carbonyldiimidazole (1.78 g, 11.0 mmol) was added, followed byiPr₂NEt (7.83 mL, 43.8 mmol). The solution was allowed to stir at 25° C.for 12 hours. Compound 9 (1.86 g, 11.0 mmol) was dissolved in 20 mL ofCH₂Cl₂ and added to the reaction mixture. The solution was stirred at25° C. for 12 hours. The solvent was removed in vacuo and the residuewas diluted with ethyl acetate and washed water and brine. The organiclayers were dried over Na₂SO₄, filtered, and evaporated. Purification byCombiflash® (stationary phase: silica gel; eluent: 66-100% EtOAc/Hexanegradient) gave Compound 81 (0.252 mg). m/z: 343.0 (M+H)⁺.

Compound 82

Compound 82 (0.252 g, 0.74 mmol) was dissolved in THF (4 mL) and 1Maqueous LiOH (1.48 mL) was added. The mixture was stirred at 25° C. for3 hours. The reaction was quenched with 1M HCl (2 mL) and the mixturewas adjusted to pH 2. The mixture was extracted with ethyl acetate. Theorganic layers were dried over Na₂SO₄, filtered, and evaporated toafford Compound 82 (0.18 g). This material was used in the next stepwithout further purification. m/z: 329.1 (M+H)⁺.

Example AR

Compound 82 (182 mg, 0.55 mmol) was dissolved in THF (7.15 mL). Compound46 (225 mg, 0.55 mmol) was added, followed by HOBt (112 mg, 0.83 mmol),iPr₂NEt (393 μL, 2.20 mmol), and EDC (194 μL, 1.10 mmol). The mixturewas stirred at 25° C. for 12 hours. The solvent was removed underreduced pressure. The residue was diluted ethyl acetate and washedsequentially with saturated aqueous Na₂CO₃, water, and brine. Theorganic phase was dried over Na₂SO₄, filtered, and evaporated.Purification by flash column chromatography (stationary phase: silicagel; eluent: 5-10% MeOH/CH₂Cl₂ gradient) gave Example AR (208 mg, 53%).m/z: 720.2 (M+H)⁺. ¹H NMR (CDCl₃) δ 8.80 (s, 1H); 7.84 (s, 1H);7.40-7.00 (m, 10H); 6.97 (s, 1H); 6.83 (m, 1H); 6.65 (br s, 1H); 5.99(m, 1H); 5.40-5.10 (m, 4H); 4.52 (m, 3H); 4.06 (m, 1H); 3.79 (m, 1H);3.34 (m, 1H); 2.97 (s, 3H); 2.90-2.60 (m, 5H); 2.50-2.40 (br s, 1H);1.80-1.20 (m, 10H).

Preparation of Example AS

Compound 85a

Compound 85a was prepared following the same procedure as Compound 4,except that 4-chloromethylthiazole (purchased from TCI America) was usedinstead of Compound 3, and methylamine was used instead ofisopropylamine.

Compound 83

To compound 85a (0.40 g, 3.12 mmol) in CH₂Cl₂ (9 mL) was addedN,N-diisopropylethylamine (1.04 mL, 5.85 mmol), followed by Compound 5(280 μL, 1.95 mmol). The reaction mixture was stirred for 3.5 hours at25° C. Solvent was removed under reduced pressure. Purification byCombiflash® (stationary phase: silica gel; eluent: 90-100% EtOAc/Hexanegradient) gave Compound 83 (0.51 g). m/z: 286.0 (M+H)⁺.

Compound 84

Compound 83 (0.51 g, 1.77 mmol) was dissolved in THF (10 mL) and 1Maqueous LiOH (3.54 mL) was added. The mixture was stirred at 25° C. for2 hours. The reaction was quenched with 1M HCl (4.8 mL) and the mixturewas adjusted to pH 2. The mixture was extracted with ethyl acetate. Theorganic layers were dried over Na₂SO₄, filtered, and evaporated toafford Compound 84 (0.430 g). This material was used in the next stepwithout further purification. m/z: 272.0 (M+H)⁺.

Example AS

Compound 84 (150 mg, 0.55 mmol) was dissolved in THF (7.15 mL). Compound8 (225 mg, 0.55 mmol) was added, followed by HOBt (112 mg, 0.83 mmol),iPr₂NEt (393 μL, 2.20 mmol), and EDC (198 μL, 1.11 mmol). The mixturewas stirred at 25° C. for 12 hours. The solvent was removed underreduced pressure. The residue was diluted ethyl acetate and washedsequentially with saturated aqueous Na₂CO₃, water, and brine. Theorganic phase was dried over Na₂SO₄, filtered, and evaporated.Purification by flash column chromatography (stationary phase: silicagel; eluent: 7% i-PrOH/CH₂Cl₂) gave Example AS (219 mg, 60%). m/z: 663.1(M+H)⁺. ¹H NMR (CDCl₃) δ 8.87 (s, 1H); 8.76 (s, 1H); 7.84 (s, 1H);7.40-7.00 (m, 10H); 6.22 (br s, 1H); 5.73 (br s, 1H); 5.22 (m, 2H); 4.50(m, 2H); 4.16 (br s, 1H); 4.05 (br s, 1H); 3.75 (m, 1H); 2.93 (s, 3H);2.90-2.60 (m, 5H); 2.90 (m, 1H); 2.31 (m, 1H); 1.60-1.30 (m, 4H);1.00-0.80 (m, 6H).

Preparation of Example AT

Compound 87

Compound 87 (386 mg) was prepared from Compound 86 following the sameprocedure used to prepare Compound 7 from Compound 6, except thatCompound 68 was used was used instead of Compound 4. m/z 286.0 (M+H)⁺

Preparation of Example AU

Compound 85b

Compound 85b was prepared following the same procedure as Compound 4,except that 4-chloromethylthiazole (obtained from TCI America) was usedinstead of Compound 3.

Compound 88

Compound 88 (341 mg) was prepared following the same procedure used toprepare Compound 83, with the exception that Compound 85b (300 mg, 1.95mmol) was used instead of Compound 68. m/z: 312.0 (M+H)⁺.

Compound 89

Compound 89 (341 mg) was prepared following the same procedure for 84,with the exception that Compound 88 (293 mg, 0.99 mmol) was used insteadof Compound 83. m/z: 298.0 (M+H)⁺.

Example AU

Example AU (226 mg, 64%) was prepared following the same procedure usedto prepare Example AS, with the exception that Compound 89 (150 mg, 0.51mmol) was used instead of Compound 84. m/z: 689.1 (M+H)⁺. ¹H NMR (CDCl₃)δ 8.87 (s, 1H); 8.74 (s, 1H); 7.83 (s, 1H); 7.40-7.00 (m, 10H); 6.21 (m,1H); 5.73 (m, 1H); 5.29 (m, 1H); 5.17 (m, 2H); 4.88 (d, J=16 Hz, 1H);4.47 (d, J=16 Hz, 1H); 4.18 (m, 1H); 3.75 (br s, 1H); 2.90-2.60 (m, 6H);2.51 (br s, 1H); 2.31 (m, 1H); 1.60-1.30 (m, 4H); 1.00-0.80 (m, 10H).

Preparation of Example AV

Compound 90

Compound 90 (190 mg) was prepared following the procedure used toprepare Compound 4, except that 4-(chloromethyl)-2-methylthiazole wasused instead of Compound 3. m/z 141.1 (M−H)

Compound 90

Compound 91 (400 mg) was prepared following the same procedure used toprepare Compound 6 except that Compound 90 was used instead of Compound4. m/z 300.0 (M+H)⁺

Compound 92

Compound 92 (188 mg) was prepared following the same procedure asCompound 7 except that Compound 91 was used instead of Compound 6. m/z284.0 (M−H)⁻

Example AV

Example AV (107 mg) was prepared following the procedure used to prepareExample C, except Compound 92 was used instead of Compound 7. ¹H NMR(CDCl₃) δ 8.76 (s, 1H), 7.78 (s, 1H), 7.27-7.07 (m, 10H), 6.93 (s, 1H),6.25 (m, 2H), 5.39 (m, 1H), 5.19 (m, 2H), 4.37-4.32 (m, 2H), 4.06 (m,1H), 3.81 (br s, 1H), 2.83 (m, 4H), 2.65 (br s, 7H), 2.28-2.22 (m, 1H),1.51-1.37 (m, 4H), 0.82 (m, 6H): m/z 677.2 (M+H)⁺

Preparation of Example AW

Compound 93

Compound 93 is commercially available from TCI, and was used withoutfurther purification.

Compound 94

To a solution of Compound 93 (500 mg, 3.76 mmol) in methanol (20 mL) wasadded thionyl chloride (0.5 mL, 6.6 mmol) dropwise. The mixture wasstirred at 60° C. for 20 minutes, and concentrated in vacuo to gaveCompound 94.

Compound 95

To a stirred solution of Compound 94 (3.7 mmol) anddiisopropylethylamine (1.4 mL, 8.3 mmol) in dichloromethane (50 mL) wasadded CDI (609 mg, 3.7 mmol). The mixture was stirred for 12 hours.Compound 9 was added, and the mixture was stirred for 12 additionalhours. Concentration and purification by flash column chromatography(0-100%: EtOAc/hexane) gave Compound 95 (100 mg). m/z 344.3 (M+H)⁺

Compound 96

Compound 96 (39 mg) was prepared following the same procedure used toprepare Compound 7 except that Compound 95 was used instead of Compound6. m/z 328.3 (M−H)⁻

Example AW

Example AW (107 mg) was prepared following the procedure for Example C,except that Compound 96 was used instead of Compound 7. ¹H NMR (CDCl₃) δ8.79 (s, 1H), 7.82 (s, 1H), 7.27-7.09 (m, 10H), 6.95 (s, 1H), 6.23 (m,1H), 6.14 (s, 1H), 5.22 (s, 3H), 4.45 (m, 2H), 4.35-4.0 (m, 3H), 3.8 (m,1H), 3.6 (m, 1H), 3.25 (s, 3H), 3.21 (m, 2H), 2.95 (s, 3H), 2.8-2.6 (m,4H), 2.0-1.4 (m, 4H), 1.25 (m, 4H), 1.05 (m, 4H): m/z 721.3 (M+H)⁺

Preparation of Examples AX and AY

Example AX

To a solution of Example I (650 mg, 1.00 mmol) in DMSO (3.5 mL) wasadded triethylamine (0.5 mL). The mixture was stirred for 30 minutes.Pyridine SO₃ was added to the mixture at 5° C. then stirred for 60minutes. The mixture was poured on to ice-water, then stirred for 30minutes. The mixture was diluted with EtOAc and washed with water, sat.NaHCO₃, and brine. Concentration gave Example AX. m/z 705.2 (M+H)⁺

Example AY

To a stirred solution of Example AX (70 mg, 0.099 mmol) and methylamine(1.5 mL) The 5 mL) was added AcOH (119 mg, 1.99 mmol). The mixture wasstirred for 2 hours. NaBH(OAc)₃ (94 mg) was added, and the mixture wasstirred for 2 hours. Concentration and purification by prep. HPLC gaveExample AY (30 mg). ¹H NMR (CDCl₃) δ 8.79 (s, 1H), 7.82 (s, 1H),7.27-7.09 (m, 10H), 6.95 (s, 1H), 6.23 (m, 1H), 6.14 (s, 1H), 5.22 (s,2H), 4.45 (m, 1H), 4.35-4.0 (m, 4H), 3.8 (m, 1H), 3.6 (m, 1H), 3.21 (m,1H), 2.95 (s, 3H), 2.93 (s, 3H), 2.8-2.6 (m, 4H), 2.0-1.4 (m, 4H), 1.25(m, 4H), 1.05 (m, 4H): m/z 720.3 (M+H)⁺

Preparation of Example AZ

Example AZ

Compound AZ (61 mg) was prepared following the procedure for Example C,except that Compound 87 was used instead of Compound 7 and Compound 79was used instead of Compound 8. ¹H NMR (CDCl₃) δ 8.77 (s, 1H), 8.72 (s,1H), 7.78 (s, 1H), 7.71 (s, 1H), 6.23 (d, 1H), 5.28-5.24 (m, 2H), 4.85(d, 1H), 4.71-4.57 (m, 2H), 4.08-4.03 (m, 1H), 3.78 (br s, 1H), 3.51 (brs, 1H), 2.87 (s, 3H), 2.33 (br s, 1H), 2.13-2.06 (m, 1H), 1.49-1.33 (m,8H), 0.93-0.80 (m, 12H): m/z 539.2 (M+H)⁺

Preparation of Examples BA and BB

Compound 97

Compound 97 is commercially available from TCI, and was used asreceived.

Compound 98

To a stirred solution of Compound 97 (1 g, 2.2 mmol) anddiisopropylethylamine (1.6 mL, 8.9 mmol) in dichloromethane (26 mL) wasadded CDI (362 mg, 2.2 mmol). The mixture was stirred for 12 hours.Compound 9 was added, and the mixture was stirred for 12 additionalhours. Concentration and purification by flash column chromatography(0-8%: MeOH/DCM) gave Compound 98 (1.2 g). m/z 608.1 (M+H)⁺

Compound 99

Compound 99 (1.2 g) was prepared following the same procedure used toprepare Compound 67, with the exception that Compound 98 was usedinstead of Compound 66. m/z 592.2 (M−H)⁻

Example BA

Example BA (111 mg) was prepared following the procedure used to prepareExample C, except that Compound 99 was used instead of Compound 7. m/z986.1 (M+H)⁺

Example BB

To a stirred solution of Example BA (111 mg, 0.113 mmol) and TFA (1.4mL) was added Et₃SiH (0.1 mL). The mixture was stirred for 60 minutes,then concentrated and partitioned with EtOAc and sat. NaHCO₃, followedby extraction with EtOAc (2×) and drying over Na₂SO₄. Concentration andpurification by flash column chromatography (0-15%: MeOH/DCM) gaveExample BB (50 mg).

¹H-NMR (CDCl₃) of 8.75 (s, 1H), 7.79 (s, 1H), 7.42 (s, 1H), 7.22-7.12(m, 9H), 6.99-6.96 (m, 2H), 6.86 (s, 1H), 6.71 (m, 2H), 5.51 (br s, 1H),5.17 (m, 2H), 4.57-4.52 (m, 1H), 4.39-4.35 (m, 2H), 4.07 (m, 1H), 3.74(br s 1H), 3.28-3.19 (m, 1H,), 3.09-2.76 (m, 6H), 3.65-2.58 (m, 3H),1.49 (m, 2H), 1.36-1.20 (m, 8H); m/z 743.2 (M+H)⁺

Preparation of Example BC

Example BC

Example BC (95 mg) was prepared following the procedure used to prepareExample C, except that Compound 29 was used instead of Compound 7, andCompound 78 was used instead of Compound 8. ¹H NMR (CDCl₃) δ 8.75 (s,1H), 7.80 (s, 1H), 6.93 (s, 1H), 6.28 (d, 1H), 6.18 (m, 1H), 5.26-5.21(m, 3H), 4.47-4.30 (m, 2H), 4.11-4.00 (m, 1H), 3.91 (br s, 1H), 3.59 (brs, 1H), 3.28 (m, 1H), 2.97-2.90 (m, 3H), 2.26-2.19 (m, 1H), 1.39-1.24(m, 10H), 1.09-1.01 (m, 6H), 0.94-0.86 (m, 6H): m/z 553.1 (M+H)⁺

Preparation of Examples BD and BE

Example BD

Example BD (148 mg) was prepared following the procedure used to prepareExample C, except that Compound 13e was used instead of Compound 7, andCompound 78 was used instead of amine 8. m/z 611.1 (M+H)⁺

Example BE

Example BD (148 mg, 0.242 mmol) was dissolved in TFA (3 mL) and allowedto stir at 25° C. for 3 hours. The solvent was removed under reducedpressure and the residue was diluted with THF (3 mL) and 2N aqueous NaOHwas added until pH 10. The mixture was allowed to stir for 20 min andextracted with EtOAc. The organic layer was washed sequentially withwater and brine, dried over Na₂SO₄, filtered, and evaporated.Purification by flash chromatography (0-10% MeOH/CH₂Cl₂) gave Example BE(109 mg). ¹H NMR (CDCl₃) δ 8.75 (s, 1H), 7.80 (s, 1H), 6.97-6.94 (d,1H), 6.90 (s, 1H), 6.32 (br s, 1H), 5.26-5.22 (m, 2H), 5.12 (d, 1H),4.51-4.39 (m, 3H), 4.25-4.22 (m, 2H), 3.87 (br s, 1H), 3.62 (br s, 1H),3.27-3.18 (m, 1H), 2.94 (s, 3H), 1.41-1.31 (m, 10H), 1.13-1.00 (m, 9H).m/z: 555.1 (M+H)⁺.

Preparation of Example BF

Compound 100

Compound 100 was prepared using the same method used to prepare Compound122, except that Compound 9 was replaced with Compound 68 (see Scheme70).

Compound 101

Compound 100 (108 mg, 0.423 mmol) was dissolved in THF (2 mL), then 847μl of 1 M LiOH/H₂O was added. After stirring overnight, 843 μl of 1 NHCl was added. Concentration gave Compound 101.

Example BF

Example BF (24 mg) was prepared following the procedure used to prepareExample C, except that Compound 101 was used instead of Compound 7. ¹HNMR (CDCl₃) δ 8.77 (s, 1H), 8.73 (s, 1H), 7.80 (s, 1H), 7.74 (s, 1H),7.27-7.10 (m, 10H), 6.55-6.52 (d, 1H), 5.84 (d, 1H), 5.21-5.19 (m, 3H),4.77-4.53 (m, 2H), 4.39 (br s, 1H), 4.11-3.99 (m, 2H), 3.81 (br s, 1H),3.58 (m, 2H), 2.86 (s, 3H), 2.81-1.72 (m, 5H), 2.04 (m, 1H), 1.85 (m,1H), 1.66-1.37 (m, 6H): m/z 665.2 (M+H)⁺

Preparation of Example BG

Example BG

Example R (102 mg, 0.137 mmol) was dissolved in THF (2 mL), then 2 mL ofethyltrifluoroactate was added. Then 1.3 eq of MeI and excess Cs₂CO₃were added. After stirring for 1 day, the mixture was partitioned withEtOAc and sat. Na₂CO₃, extracted with EtOAc (2×), and dried over Na₂SO₄.Purification by flash chromatography (0-20% MeOH/CH₂Cl₂) gave Example BG(6.5 mg). ¹H NMR (CD₃OD) δ 9.94 (s, 1H), 8.27 (s, 1H), 7.73 (s, 1H),7.30-7.10 (m, 10H), 5.29, 5.17 (d 2H), 4.72 (s, 3H), 4.29 (m, 1H), 4.15(br s, 1H), 3.83 (br s, 1H), 3.61 (m, 2H), 3.07 (s, 3H), 2.93 (m, 2H),2.82-2.70 (m, 4H), 2.68-2.58 (m, 2H), 2.42 (s, 3H), 2.05 (m, 2H),1.70-1.40 (m, 10H). m/z: 720.2 (M+H)⁺.

Preparation of Example BH

Example BH

Example BH (78 mg) was prepared following the procedure used to prepareExample C, except that Compound 87 was used instead of Compound 7, andCompound 46 was used instead of Compound 8. ¹H NMR (CDCl₃) δ 8.73 (s,1H), 8.68 (s, 1H), 7.76 (s, 1H), 7.68 (s, 1H), 7.18-7.09 (m, 10H), 6.26(m, 1H), 5.76 (m, 1H), 5.22-5.18 (m, 4H), 4.71-4.65 (d, 1H), 4.46-4.40(d, 1H), 4.11-4.04 (m, 2H), 3.81 (br s, 1H), 3.14 (br s, 1H), 2.83 (s,3H), 2.76-2.52 (m, 4H), 1.88 (m, 1H), 1.51-1.37 (m, 2H), 0.73-0.69 (m,6H) m/z 663.2 (M+H)⁺

Preparation of Examples BI and BJ

Example BI

Example BI (1.78 g) was prepared following the procedure used to prepareExample C, except that Compound 99 was used instead of Compound 7, andCompound 46 was used instead of Compound 8. m/z 986.1 (M+H)⁺

Example BJ

Example BJ (728 mg) was prepared following the procedure used to prepareExample BB, except that Example BI was used instead of Example BA.¹H-NMR (CDCl₃) @@8.75 (s, 1H), 7.79 (s, 1H), 7.42 (s, 1H), 7.22-7.12 (m,9H), 6.99-6.96 (m, 2H), 6.86 (s, 1H), 6.71 (m, 2H), 5.51 (br s, 1H),5.17 (m, 2H), 4.57-4.52 (m, 1H), 4.39-4.35 (m, 2H), 4.07 (m, 1H), 3.74(br s 1H), 3.28-3.19 (m, 1H,), 3.09-2.76 (m, 6H), 3.65-2.58 (m, 3H),1.49 (m, 2H), 1.36-1.20 (m, 8H); m/z 743.2 (M+H)⁺

Preparation of Compounds 104-115

Compound 102

Compound 102 is commercially available from Aldrich Chemical Co., andwas used without further purification.

Compound 103

Compound 102 (5.5 mmol) was suspended in MeCN (55 mL) and DIPEA (8.25mmol) was added. Carbonyl diimidazole (5.5 mmol) was diluted in MeCN (20mL) and the solution added slowly to the reaction mixture over 45 min.The resulting mixture was allowed to age overnight. Compound 9 (5.5mmol) was diluted in MeCN (10 mL) and treated with DIPEA (8.25 mmol)before being added to the reaction mixture, which was then allowed toage overnight. The volatiles were removed in vacuo and the residue takenup in EtOAc (50 mL) and washed with 1M HCl (50 mL). The layers wereseparated and the aqueous layer extracted with EtOAc (3×50 mL). Thecombined organic layers were washed with sat. Na₂CO₃ until the pH of thewashes was ˜pH 8. A brine wash (30 mL) was followed by drying overanhydrous MgSO₄. Following concentration in vacuo, the residue waspurified on SiO₂ (0-65% EtOAc/hex) to provide 0.340 g (20%) of Compound103 as an amorphous white solid (m/z 314.0 (M+H)⁺).

Compound 104

Compound 103 (1.1 mmol) was diluted in THF (5 mL) and treated withfreshly prepared 1M LiOH (2.2 mmol). The biphasic reaction was stirredvigorously for 2 h before being quenched with 1M HCl (3 mmol). Thereaction was extracted with EtOAc (5×15 mL) and the combined organicswere washed with brine (30 mL), dried over anhydrous Na₂SO₄ andconcentrated to provide 0.282 g (86%) of Compound 104 as an amorphouswhite powder that was used with further purification ¹H-NMR (CDCl₃, 300MHz): 7.06 (s, 1H); 4.37 (s, 1H); 3.28 (p, J=6.9 Hz, 1H); 3.00 (s, 3H);1.62 (s, 6H); 1.39 (d, J=6.9 Hz, 6H).

Compound 105

Compound 105 is commercially available from Aldrich Chemical Co., andwas used without further purification.

Compound 106

Racemic Compound 105 (12.2 mmol) was diluted in MeOH (100 mL).HCl/dioxane solution (4M, 25 mmol) was added and the solution wasrefluxed overnight. Volatiles were removed in vacuo to produce 2.60 g(97%) of Compound 106 as a racemic mixture. The foamy white solid wasused without further purification (m/z 147.0 (M+H)⁺).

Compound 107

Compound 106 (5 mmol) was diluted in MeCN (65 mL) and treated with DIPEA(25 mmol). The resulting solution was added slowly via addition funnelto a solution of CDI (5 mmol) in MeCN (30 mL) and allowed to ageovernight. Compound 9 (5 mmol) and DIPEA (3 mmol) were added to thereaction solution which was allowed to age overnight. The volatiles wereremoved in vacuo and the residue was taken up in EtOAc and sat. Na₂CO₃(30 mL each). The aqueous layer was extracted with EtOAc (3×25 mL) andthe combined organics were washed with brine (50 mL) and dried overanhydrous MgSO₄. Following concentration in vacuo, purification bycolumn chromatography on SiO₂ (0-10% MeOH/DCM) provided 0.36 g (21%) ofracemic Compound 107 as a yellow oil (m/z 343.1 (M+H)⁺).

Compound 108

Compound 107 (1.05 mmol) was taken up in THF (5 mL) and treated withfreshly prepared 1M LiOH solution (2.1 mmol). The solution was stirredvigorously for 2 h and quenched with 1M HCl (2.1 mmol). The volatileswere removed in vacuo, and the resulting oil was azeotroped with tolueneuntil a quantitative yield of racemic Compound 107 was produced as anamorphous white solid that was used without further purification (m/z329.1 (M+H)⁺).

Compound 109

Compound 109 is commercially available from Bachem, and was used asreceived.

Compound 110

Compound 109 (4.1 mmol) was diluted in DCM (5 mL) and treated withN-methylmorpholine (8.2 mmol). This solution was added slowly to a DCM(5 mL) solution of 4-nitrophenyl chloroformate (4.1 mmol) at 0° C. Thereaction was then allowed to warm to room temperature overnight. Thevolatiles were removed in vacuo and the residue was taken up in EtOAcand sat. Na₂CO₃. The aqueous layer was extracted with EtOAc (3×10 mL)and the combined organics were washed with brine (30 mL) prior to beingdried over anhydrous Na₂SO₄. Following concentration in vacuo, theresidue was purified by column chromatography on SiO₂ (0-25% EtOAc/Hex)to produce 0.75 g (51%) of Compound 110 as an amorphous white solid (m/z354.8 (M+H)⁺).

Compound 111

Compound 110 (1.1 mmol) was diluted in THF (3:5 mL). Compound 9 (1.4mmol) was diluted in THF (3 mL), treated with Et₃N (2.8 mmol) andtransferred to the reaction solution. DMAP (0.11 mmol) was added and thereaction was heated to 70° C. for 2 h. After cooling to roomtemperature, EtOAc (10 mL) and sat. Na₂CO₃ were added. The aqueous phasewas extracted with EtOAc (3×10 mL) and the combined organics were washedwith sat. Na₂CO₃, H₂O, and brine (15 mL each). After drying overanhydrous MgSO₄, volatiles were removed in vacuo and the residue waspurified by column chromatography on SiO₂ (0-50% EA/hex) to produce0.346 g (82%) of Compound 111 (m/z 386.0 (M+H)⁺).

Compound 112

Compound 111 (0.88 mmol) was taken up in THF (4 mL) and treated withfreshly prepared 1M LiOH (1.8 mmol). The reaction mixture was stirredvigorously for 1.5 h and quenched with 1M HCl (2.5 mmol). The reactionmixture was extracted with EtOAc (3×10 mL), and the combined organicswere washed with brine (30 mL) and dried over anhydrous Na₂SO₄.Concentration in vacuo produced 0.300 g (92%) of Compound 112 as acolorless film that was used without further purification (m/z 372.0(M+H)⁺).

Compound 113

Compound 113 is commercially available from Chem-Impex, and was usedwithout further purification.

Compound 114

Compound 113 (3.2 mmol) was diluted in THF (15 mL). TMSCHN₂ (3.2 mmol)was added slowly, followed by MeOH (5 mL). The solution rapidly becamecolorless, and heavy evolution of gas was observed. After agingovernight, the volatiles were removed in vacuo and the residue purifiedby column chromatography on SiO₂ (0-50% EtOAc/hex) to produce 0.805 g(52%) of Compound 114 (m/z 505.2 (M+Na)⁺).

Compound 115

Compound 114 (1.7 mmol) was diluted in DMF (4 mL) and piperidine (1 mL)was added. After 30 min, the volatiles were removed in vacuo and theresidue was purified by column chromatography on SiO₂ (0-5% MeOH/DCM) toprovide 0.414 (94%) of Compound 115 as an amorphous white solid (m/z261.0 (M+H)⁺).

Preparation of Example BK

Compound BK

Compound 79 (0.70 mmol) and Compound 29 (0.91 mmol) were combined in THF(7 mL). HOBt (0.91 mmol), DIPEA (1.05 mmol) and EDC (0.91 mmol) wereadded consecutively at room temperature and the reaction was allowed toage overnight. The volatiles were removed in vacuo and the residue takenup in 3/1 CHCl₃/IPA and sat. Na₂CO₃ (15 mL each). The aqueous layer wasextracted with 3/1 CHCl₃/IPA (3×10 mL) and the combined organics werewashed with sat. Na₂CO₃, water, and brine (15 mL each). Following dryingover anhydrous MgSO₄, the volatiles were removed in vacuo and theresidue was purified by column chromatography on SiO₂ (0-10% MeOH/DCM)to produce 8.5 mg (2%) of Compound BK m/z 581.2 (M+H)⁺; ¹H-NMR (CDCl₃,300 MHz): 8.91 (s, 1H); 7.89 (s, 1H); 7.15 (s, 1H); 6.52-6.0 (br m, 2H);5.26 (s, 2H); 5.18 (br d, J=8.1 Hz, 1H); 4.55 (s, 2H); 4.06 (br s, 1H);3.79 (br s, 1H); 3.48 (m, 2H); 3.09 (s, 3H, minor rotamer); 3.01 (s, 3H,major rotamer); 2.34 (m, 1H); 1.60-1.30 (m, 8H); 1.42 (d, J=6.9 Hz, 6H);0.98 (t, J=7.2 Hz, 6H); 0.86 (m, 6H).

Preparation of Example BL

Example BL

Example BL was prepared in a similar fashion to Example BK usingCompound 104 (0.26 mmol) and Compound 8 (0.29 mmol) to produce 0.087 g(64%) of Example BL as an amorphous white solid m/z 691.3 (M+H)⁺; ¹H-NMR(CDCl₃, 300 MHz): 8.82 (s, 1H); 7.82 (s, 1H); 7.30-7.10 (m, 11H); 7.06(s, 1H); 6.54 (d, J=9.6 Hz, 1H); 5.89 (d, J=8.4 Hz, 1H); 5.22 (s, 1H);5.07 (m, 1H); 4.45 (AB d, J=16.5 Hz, 1H); 4.37 (AB d, J=15.6 Hz, 1H);4.07 (m, 1H); 3.68 (m, 1H); 3.40 (m, 1H); 3.06 (s, 3H, minor rotamer);2.89 (s, 3H, major rotamer); 2.90-2.54 (m, 4H); 1.60-1.25 (m, 16H).

Preparation of Examples BMa and BMb

Examples BMa and BMb

Examples BMa and BMb were prepared in a similar fashion to Compound BKusing racemic Compound 108 (0.36 mmol) and Compound 8 (0.28 mmol). Theenantiomeric products were separated by preparatory HPLC (Chiralcel OD-H(250×4.6 mm, 70:30 Heptane/IPA, 30 min) to produce 0.008 g (4%) ofenantiomer BMa (HPLC R_(T)=11.71 min) m/z 720.3 (M+H)⁺; ¹H-NMR (CDCl₃,300 MHz): 8.73 (s, 1H); 7.78 (s, 1H); 7.41 (br s, 1H); 7.30-7.00 (m,11H); 6.94 (s, 1H); 5.40 (br s, 1H); 5.18 (br s, 2H); 4.56 (AB d, J=15Hz, 1H); 4.48 (AB d, J=16 Hz, 1H); 4.39 (br s, 1H); 4.05 (br s, 1H);3.73 (br s, 1H); 3.25 (s, 3H, minor rotamer); 3.23 (m, 1H); 2.98 (s, 3H,major rotamer); 2.82-2.30 (m, 10H); 1.60-1.20 (m, 6H); 1.32 (d, J=7 Hz,6H) and 0.010 g (5%) of enantiomer BMb (HPLC R_(T)=15.41 min). (m/z720.3 (M+H)⁺; ¹H-NMR (CDCl₃, 300 MHz): 8.78 (s, 1H); 7.83 (s, 1H); 7.38(br d, J=8 Hz, 1H); 7.30-7.7.05 (m, 11H); 7.02 (s, 1H); 5.52 (d, J=9 Hz,1H); 5.25 (AB d, J=13 Hz, 1H); 5.21 (AB d, J=13 Hz, 1H); 4.85-4.62 (m,2H); 4.44 (d, J=16 Hz, 1H); 3.99 (br s, 1H); 3.78 (br s, 1H); 3.37 (brs, 3H, minor rotamer); 3.26 (m, 1H); 3.07 (s, 3H, major rotamer); 2.77(s, 6H); 2.86-2.60 (m, 4H); 1.6-1.3 (m, 6H); 1.35 (d, J=7 Hz, 6H).

Preparation of Examples BO and BO

Example BP

Example BN was prepared in a similar fashion to Example BK usingCompound 112 (0.78 mmol) and Compound 8 (0.60 mmol) to produce 0.227 g(50%) of Compound BN as colorless film. (m/z 763.3 (M+H)⁺).

Example BO

Example BO was prepared in a similar fashion to Example AM using ExampleBN (0.29 mmol) to produce 0.149 g (72%) of Example BO as an amorphouswhite solid. (m/z 707.3 (M+H)⁺; ¹H-NMR (CDCl₃, 300 MHz): 8.82 (s, 1H);7.84 (s, 1H); 7.26-7.03 (m, 11H); 6.99 (s, 1H); 6.69 (d, J=9.6, 1H);6.42 (br s, 1H); 5.47 (br d, J=8.7 Hz, 1H); 5.27 (AB d, J=13 Hz, 1H);5.22 (AB d, J=13 Hz, 1H); 4.55 (AB d, J=16 Hz, 1H); 4.43 (AB d, J=16 Hz,1H); 4.18 (m, 1H); 4.00 (m, 2H); 3.72 (br s, 1H); 2.25 (m, 1H); 2.99 (s,3H); 2.84-2.60 (m, 3H); 2.54-2.42 (m, 1H); 1.64-1.12 (m, 4H); 1.37 (d,J=7 Hz, 6H); 1.11 (d, J=6 Hz, 3H).

Preparation of Examples BP-BR

Example BP

Example BP was prepared in a similar fashion to Example BK usingCompound 52 (0.22 mmol) and Compound 78 (0.20 mmol) to produce 0.091 g(71%) of Example BP as colorless film (m/z 654.2 (M+H)⁺).

Example BQ

Example BQ (0.14 mmol) was treated with 4M HCl in dioxane (2 mL) toproduce a white precipitate within 5 min. The solvents were removed, andthe solid was taken up in MeOH. Concentration in vacuo afforded 0.083 g(99%) of the HCl salt of Example BQ as a colorless film (m/z 554.1(M+H)⁺; ¹H-NMR (CD₃OD, 300 MHz): 10.03 (s, 1H); 8.41 (s, 1H); 7.81 (s,1H); 5.48 (s, 2H, minor rotamer); 5.35 (s, 2H, major rotamer); 4.74 (s,2H); 4.34 (br s, 1H); 3.90 (br s, 1H); 3.78-3.54 (m, 2H); 3.20-2.98 (m,5H); 2.20 (br s, 1H); 2.07 (br s, 1H); 1.60-1.4 (m, 10H); 1.12 (m, 6H).

Example BR

Example BQ (0.11 mmol) was taken up in MeOH (1.5 mL). Formaldehyde (37%in H₂O, 13.4 mmol) was added and aged 10 min. NaHB(OAc)₃ (0.324 mmol)was added, and the reaction mixture was allowed to age at roomtemperature overnight. More formaldehyde (13.4 mmol) and NaHB(OAc)₃(0.324 mmol) were added and allowed to age an additional 6 h at roomtemperature. The solvents were removed in vacuo and the product wasisolated by preparatory HPLC to produce 0.058 g (77%) of the TFA salt ofExample BR as an amorphous solid. m/z 582.3 (M+H)⁺; ¹H-NMR (CD₃OD, 300MHz): 9.07 (s, 1H); 7.91 (s, 1H); 7.25 (s, 1H); 5.47 (s, 2H, minorrotamer); 5.28 (s, 2H, major rotamer); 4.59 (AB d, J=0.16 Hz, 1H); 4.53(AB d, J=16 Hz, 1H); 4.31 (dd, J=9.2, 5 Hz, 1H); 3.88 (m, 1H); 3.59 (m,1H); 3.32 (m, 1H); 3.20 (m, 2H); 2.98 (s, 3H); 2.89 (br s, 6H); 2.23 (m,1H); 2.00 (m, 1H); 1.44 (m, 4H); 1.37 (d, J=7 Hz, 6H); 1.10 (m, 6H).

Preparation of Examples BS and BT

Compound 116

Compound 116 was prepared in a similar fashion to Compound 75 usingCompound 4 (0.76 mmol) and Compound 47 (0.64 mmol) to produce 0.218 g(90%) of Compound 116 as a foamy white solid (m/z 384.1 (M+H)⁺).

Example BS

Example BS was prepared in a similar fashion to Example BK usingCompound 116 (0.28 mmol) and Compound 8 (0.25 mmol) to produce 0.139 g(72%) of Example BS as a colorless film (m/z 775.3 (M+H)⁺).

Example BT

Example BT was prepared in a similar fashion to Example AM using ExampleBU (0.18 mmol) to produce 0.080 g (62%) of Example BT as an amorphouswhite solid. m/z 719.3 (M+H)⁺; ¹H-NMR (CDCl₃, 300 MHz): 8.79 (s, 1H);7.82 (s, 1H); 7.27-7.0 (m, 10H); 6.98-6.82 (m, 1H); 6.85 (s, 1H); 6.44(br s, 1H); 5.30 (s, 2H, minor rotamer); 5.22 (s, 2H, major rotamer);5.04 (br s, 1H); 4.62 (AB d, J=15 Hz, 1H); 4.54 (AB d, J=15 Hz, 1H);4.27 (br s, 1H); 4.11 (br s, 1H); 3.97 (br d, J=10 Hz, 1H); 3.82, br s,1H); 3.57 (br s, 1H); 3.40-3.10 (m, 2H); 2.80-2.60 (m, 4H); 2.55 (m,1H); 1.54 (m, 2H); 1.46-1.30 (m, 2H); 1.35 (d, J=7 Hz, 6H); 0.94-0.72(m, 4H).

Preparation of Examples BU and BV

Compound 117

Compound 117 was prepared in a similar fashion to Compound 13d exceptthat Compound 4 (1.5 mmol) and the L-enantiomer of Compound 10d (1.15mmol) were used to ultimately produce 0.328 g (88%) of Compound 190 as afoamy white solid (m/z 398.1 (M+H)⁺).

Example BU

Example BU was prepared in a similar fashion to Example AL usingCompound 117 (0.33 mmol) and Compound 8 (0.30 mmol) to produce 0.196 g(84%) of Example BU as an amorphous white solid (m/z 789.3 (M+H)⁺).

Example BV

Example BV was prepared in a similar fashion to Example AM using ExampleBU (0.29 mmol) to produce 0.140 g (77%) of Example BV as an amorphouswhite solid. m/z 733.3 (M+H)⁺; ¹H-NMR (CDCl₃, 300 MHz): 8.80 (s, 1H);7.84 (s, 1H); 7.27-7.10 (m, 10H); 6.70-6.10 (m, 1H); 6.86 (s, 1H); 6.20(br d, J=7 Hz, 1H); 5.24 (s, 2H); 4.81 (br d, J=7 Hz, 1H); 4.82 (s, 2H);4.34 (br d, J=7 Hz, 1H); 4.16 (br s, 1H); 4.07 (br d, J=6 Hz, 1H); 3.86(br s, 1H); 3.38 (br s, 1H); 2.69 (m, 6H); 1.62-1.50 (m, 2H); 1.50-1.34(m, 2H); 1.38 (m, 6H); 1.13 (d, J=6 Hz, 3H); 0.98-0.76 (m, 4H).

Preparation of Examples BW and BX

Example BW

Example BW was prepared in a similar fashion to Example BK usingCompound 75 (0.27 mmol) and Compound 46 (0.24 mmol) to provide 0.154 g(86%) of Example BW as an amorphous white solid (m/z 733.3 (M+H)⁺).

Example BX

Example BX was prepared in a similar fashion to Example AM using ExampleBW (0.21 mmol) to provide 0.091 g (98%) of the TFA salt of Example BX asan amorphous white solid. m/z 677.5 (M+H)⁺; ¹H-NMR (CDCl₃, 300 MHz):8.83 (s, 1H); 8.77 (s, 1H); 7.84 (s, 1H); 7.77 (s, 1H); 7.27-7.00 (m,10H); 6.62 (d, J=9 Hz, 1H); 6.44 (d, J=6 Hz, 1H); 5.35 (d, J=10 Hz, 1H);5.24 (s, 2H); 4.69 (AB d, J=15 Hz, 1H); 4.62 (AB d, J=16 Hz, 1H); 4.14(br m, 2H); 3.96-3.78 (m, 2H); 3.51 (dd, J=11, 4.5 Hz, 1H); 3.38 (br s,1H); 2.82-2.58 (m, 4H); 2.41 (m, 1H); 1.70-1.24 (m, 4H); 1.20-0.88 (m,2H); 0.88-0.54 (m, 2H).

Preparation of Examples BY and BZ

Compound 118

Compound 118 was prepared in a similar fashion to Compound 104 exceptthat Compound 115 (0.40 mmol) was used instead of Compound 102, whichwas reacted with Compound 9 (0.48 mmol) to ultimately provide 0.075 g(89%) of Compound 118 as a foamy white solid (m/z 443.4 (M+H)⁺).

Example BY

Example BY was prepared in a similar fashion to Example BM usingCompound 118 (0.17 mmol) and Compound 8 (0.15 mmol) to produce 0.079 g(62%) of Example BY as an amorphous white solid (m/z 834.3 (M+H)⁺).

Example BZ

Example BZ was prepared in a similar fashion to Example BQ using ExampleBY (0.095 mmol) to provide 0.082 g (99%) of the HCl salt of Example BZas an amorphous white solid m/z 734.2 (M+H)⁺; ¹H-NMR (DMSO-d₆, 300 MHz):8.08 (s, 1H); 7.86 (br m, 3H); 7.58 (d, J=9 Hz, 1H); 7.25-7.00 (m, 11H);6.32 (br s, 1H); 5.16 (s, 2H); 4.99 (br m, 4H); 4.48 (AB d, J=15 Hz,1H); 4.43 (AB d, J=15 Hz, 1H); 4.02 (m, 1H); 3.89 (m, 1H); 3.63 (m, 1H);3.22 (hep, J=7 Hz, 1H); 2.87 (s, 3H); 2.76-2.56 (m, 4H); 1.58-1.15 (m,10H); 1.29 (d, J=7 Hz, 6H).

Preparation of Example Ca

Example CA

Example R (0.11 mmol) was diluted in DCM (1 mL) and treated with4-morpholinecarbonyl chloride (0.13 mmol) and DIPEA (0.16 mmol). After 2h, volatiles were removed in vacuo and the residue was purified bycolumn chromatography on SiO₂ (0-20% MeOH/DCM) to afford 0.068 g (76%)of Example CA as an amorphous white solid m/z 819.1 (M+H)⁺; ¹H-NMR(CDCl₃, 300 MHz): 8.82 (s, 1H); 7.85 (s, 1H); 7.27-7.07 (m, 12H); 6.94(s, 1H); 6.26 (br s, 1H); 5.73 (d, J=8 Hz, 1H); 5.28 (AB d, J=13 Hz,1H); 5.22 (AB d, J=13 Hz, 1H); 4.50 (AB d, J=16 Hz, 1H); 4.44 (AB d,J=16 Hz, 1H); 4.17 (m, 1H); 3.98 (br s, 1H) 3.76 (br s, 1H); 3.68 (br s,1H); 3.60 (m, 4H); 3.40 (m, 2H), 3.32 (m, 4H); 2.97 (s, 3H); 2.87 (dd,J=13, 5 Hz, 2H); 2.73, (m, 2H); 2.57 (m, 2H); 1.79 (m, 2H); 1.60-1.20(m, 6H); 1.37 (d, J=7 Hz, 6H).

Preparation of Compound CB

Example CB

Example AF (0.15 mmol) was diluted in THF (1 mL) and treated withmorpholine (0.61 mmol), HOBt (0.18 mmol) and finally EDC (0.18 mmol).The reaction mixture was allowed to age overnight. The reaction mixturewas then diluted in EtOAc and sat. Na₂CO₃. The aqueous layer wasextracted with EtOAc and the combined organic layers were washed withbrine, dried over anhydrous MgSO₄ and concentrated in vacuo. Theresulting residue was purified via preparatory HPLC to provide 0.024 g(20%) of Example CB as an amorphous white solid. m/z 790.4 (M+H)⁺;¹H-NMR (CDCl₃, 300 MHz): 8.81 (s, 1H); 7.84 (s, 1H); 7.27-7.10 (m, 10H);6.96 (s, 1H); 6.78 (d, J=8 Hz, 1H); 6.67 (s, 1H); 5.36 (d, J=9 Hz, 1H);5.27 (AB d, J=13 Hz, 1H); 5.20 (AB d, J=13 Hz, 1H); 4.59 (s, 1H); 4.51(s, 2H); 4.02 (m, 1H); 3.80-3.30 (m, 10H); 2.98 (s, 3H); 2.90-2.45 (m,6H); 1.52 (m, 2H); 1.39 (d, J=7 Hz, 6H); 1.32 (m, 2H).

Preparation of Compound Cc

Example CC

Example CC was prepared in a similar fashion to Example CB except thatN-methylpiperazine (0.16 mmol) was reacted with Compound AF (0.10 mmol)instead of morpholine and DIPEA (0.19 mmol) was added to produce 0.009 g(11%) of Example CC as an amorphous white solid m/z 803.4 (M+H)⁺; ¹H-NMR(CDCl₃, 300 MHz): 8.80 (s, 1H); 7.84 (s, 1H); 7.27-7.10 (m, 11H); 6.91(s, 1H); 6.78 (m, 2H); 5.27 (AB d, J=13 Hz, 1H); 5.21 (AB d, J=13 Hz,1H); 4.59 (m, 1H); 4.49 (AB d, J=16 Hz, 4.44 (AB d, J=16 Hz, 1H); 4.01(m, 1H); 3.90-3.40 (m, 4H); 3.27 (hep, J=7 Hz, 1H); 3.10-2.90 (m, 1H);2.97 (s, 3H); 2.90-2.30 (m, 11H); 1.60-1.25 (m, 6H); 1.37 (d, J=7 Hz,6H).

Preparation of Example CD

Example CD

To a solution of Example R (30.5 mg, 0.043 mmol) in methanol (1.5 mL)was added formaldehyde (1 mL, 37% in H₂O). After stirring for 10minutes, NaBH(OAc)₃ (49 mg, 0.23 mmol) was added and the resultingmixture was stirred for 10 h. The reaction was monitored with LC/MS.When LC/MS indicated the absence of starting material Example R, thereaction mixture was evaporated to dryness, and filtered through acotton plug. The crude product was then purified through CombiFlash (10%MeOH/CH₂Cl₂) to give 29.7 mg of Example CD ¹H-NMR (CDCl₃, 500 MHz): 8.78(s, 1H); 7.83 (s, 1H); 7.12-7.22 (m, 10H); 6.85 (s, 1H); 5.83 (d, 1H,J=8.5 Hz), 5.23 (d_(AB), 2H, J=13.1 Hz); 4.49 (d_(AB), 2H, J=16.5 Hz);4.29 (m, 1H); 4.15 (m, 1H); 3.75 (m, 1H); 3.30 (m, 1H); 2.93 (s, 3H);2.87 (dd, 1H, J1=5.5 Hz, J2=13.5 Hz); 2.72 (m, 2H); 2.66 (dd, J1=7.3 Hz,J2=13.3 Hz), 2.47 (br s, 1H), 2.36 (br s, 1H), 2.23 (s, 6H), 1.91 (m,2H), 1.56 (m, 2H), 1.40 (m, 2H), 1.40 (d, 6H, J=6.8 Hz). m/z 734 (M+H)⁺;756 (M+Na)⁺;

Preparation of Example CE

Compound 119

Compound 119 is commercially available from Aldrich, and was used asreceived.

Compound 120

A mixture of Compound 119 (200 mg, 0.91 mmol), Compound 8 (373.7 mg,0.91 mmol), EDC (212 mg, 1.37 mmol), HOBt (160.3 mg, 1.19 mmol) andiPr₂NEt (794.7 μL, 4.56 mmol) in THF was stirred for 10 h at roomtemperature. The mixture was then evaporated to a small volume andpurified by CombiFlash (eluted with 1 to 10% MeOH/CH₂Cl₂). The fractionscontaining the target Compounds were collected and re-purified byCombiFlash (40-100% EtOAc/hexanes) to give 449 mg of Compound 120 asoil. (m/z 611.0 (M+H)⁺).

Example CE

Compound 120 (449 mg, 0.74 mmol) was treated with HCl/dioxane (3 mL).The resulting mixture was evaporated to dryness and lyophilized toprovide 373.6 mg of a white solid.

To a solution of the above white compound (52.5 mg, 0.096 mmol) inCH₂Cl₂ (10 mL) was added Compound 9 (19.8 mg, 0.096 mmol), CDI (15.6 mg,0.096 mmol) followed by iPr₂NEt (33.4 μL, 0.192 mmol). The mixture wasstirred for 20 h before it was evaporated to dryness. The mixture wasadded CH₂Cl₂, then filtered through a cotton plug. The filtrate wasevaporated to dryness and purified with CombiFlash. The fractions withExample CE was collected and re-purified on the TLC to give 15.1 mg ofExample CE. ¹H-NMR (CDCl₃, 300 MHz): 8.79 (s, 1H); 7.82 (s, 1H);7.09-7.27 (m, 10H), 6.94 (s, 1H); 6.25 (d, 2H, J=8.7 Hz); 5.23 (s, 2H);5.17 (br s, 1H); 4.43 (d_(AB), 2H, J=16.5 Hz); 4.29 (m, 1H); 4.13 (m,1H), 3.76 (m, 2H); 3.48 (m, 1H); 3.29 (s, 3H); 3.25 (m, 1H), 2.94 (s,3H), 2.65-2.82 (m, 4H), 1.75 (m, 2H), 1.54 (m, 2H), 1.39 (d, 5H, J=6.9Hz). m/z 707 (M+H)⁺; 729 (M+Na)⁺.

Preparation of Example CF

Example CF

Example CF was prepared using the same method as Example CE, except thatCompound 9 was replaced with Compound 68. ¹H-NMR (CDCl₃, 300 MHz): 8.79(s, 1H); 8.74 (s, 1H), 7.81 (s, 1H), 7.73 (s, 1H); 7.12-7.27 (m, 10H);6.15 (d, 1H, J=8.7 Hz), 5.39 (d, 1H, J=6.8 Hz); 5.21 (s, 2H), 5.06 (d,J=9.1 Hz, 1H); 4.64 (d_(AB), 2H, J=15.5 Hz); 4.28 (m, 1H); 4.134 (m,1H), 3.79 (m, 1H), 3.70 (m, 1H); 3.34 (m, 1H); 3.28 (s, 3H); 2.87 (s,3H); 2.72 (m, 4H); 1.57 (m, 2H); 1.50 (m, 2H). (m/z 665.2 (M+H)⁺; 687.3(M+Na)⁺.

Preparation of Compound CG

Compound 121

Compound 121 is commercially available from Aldrich, and was used asreceived.

Compound 122

To a suspension of Compound 121 (2.05 g, 11.3 mmol) in CH₂Cl₂ (40 mL)was added. iPr₂NEt (5.87 mL, 33.9 mmol) followed by CDI (1.86 g, 11.3mmol). The resulting mixture was stirred at room temperature for 6 h,then Compound 9 (2.33 g, 11.3 mmol) was added. The resulting mixture wasstirred for another 10 h before it was evaporated to dryness. Themixture was re-dissolved in CH₂Cl₂ and the solid was removed byfiltration. The filtrate was evaporated to dryness and purified byCombiFlash (eluted with 20-80% EtOAc/hexanes) to give 3.2 g of Compound207 as a pale yellow oil. m/z 298.0 (M+H)⁺.

Compound 123

To a solution of Compound 122 (3.2 g, 10.8 mmol) in THF (100 mL) wasadded freshly prepared 1M LiOH (10.8 mmol). The biphasic reaction wasstirred vigorously at room temperature for 16 h before being quenchedwith 1M HCl. The pH of the mixture was adjusted to 2.5-3, and thenevaporated to a small volume. The mixture was partitioned between CH₂Cl₂and brine (50 mL), the aqueous layer was separated and extracted withCH₂Cl₂ twice. The combined CH₂Cl₂ layers were dried over anhydrousNa₂SO₄ and concentrated to give 3.37 g of Compound 123 a pale yellow oilthat is used with further purification. m/z 316.0 (M+H)⁺, 338 (M+Na)⁺;

Example CG

Example CG was prepared following the same procedure for Example Cinstead that Compound 123 was used instead of Compound 7. ¹H-NMR (CDCl₃,500 MHz): 8.80 (s, 1H); 7.83 (s, 1H), 7.11-7.26 (m, 10H), 6.96 (s, 1H);7.12-7.27 (m, 10H); 6.52 (br s, 1H), 6.40 (br s, 1H), 5.23 (s, 2H), 5.20(m, 1H), 4.44 (d_(AB), 2H, J=15.5 Hz), 4.39 (m, 1H), 4.11 (m, 1H), 3.80(m, 1H), 3.61 (m, 2H), 3.28 (sep, 1H, J=7.0 Hz); 2.94 (s, 3H), 2.79 (dd,1H, J1=6.1 Hz, J2=13.4 Hz); 2.71 (m, 3H), 1.93 (m, 1H), 1.71 (m, 1H),1.54 (m, 1H), 1.38 (d, 6H, J=7.0 Hz) 1.37 (m, 1H). (:)⁺; m/z 707.3(M+H)⁺), 729.2 (M+Na)⁺.

Preparation of Compound 100

Compound 100 was prepared using the same method used to prepare Compound122, except that Compound 9 was replaced with Compound 68.

Preparation of Example CH

Compounds 124 and 125

To a solution of Compound 29 (135 mg, 0.43 mmol) and Compound 22 (116mg, 0.43 mmol) in THF (5 mL) were added HOBt (70 mg, 0.52 mmol), EDC (94μL, 0.52 mmol), and diisopropylethylamine (150 μL, 0.83 mmol). Themixture was stirred for 12 hours and concentrated. Purification byreverse HPLC gave Compound 124 (70 mg) and Compound 125 (120 mg).Compound 124: ¹H-NMR (CDCl₃) c 7.2-7.1 (10H, m), 7.0 (2H, s), 6.45 (2H,m), 6.15 (2H, m), 4.45 (4H, s), 4.1 (2H, m), 3.96 (2H, m), 3.3 (2H, m),2.98 (6H, s), 2.7 (4H, m), 2.1 (2H, m), 1.6-1.3 (16H, m), 0.90 (12H, m).m/z 859.3 (M+H)⁺; Compound 125: m/z 564.3 (M+H)⁺

Compound 126

To a solution of Compound 125 (120 mg, 0.21 mmol) in CH₃CN (1 mL) wasadded 37% formaldehyde solution (17 μL, 0.23 mmol), followed by HOAc (24μl, 0.42 mmol). The mixture was stirred for 2 hours, and NaBH(OAc)₃ (140mg, 0.63 mmol) was added. The mixture was stirred for 2 additional hoursand diluted with EtOAc. The organic phase was washed with saturatedNa₂CO₃ solution, water, and brine, and dried over Na₂SO₄. Concentrationgave Compound 126, which was used in the next step without furtherpurification. m/z 578.3 (M+H)⁺

Example CH

Example CH (26 mg) was prepared following the procedure used to prepareExample L, except that Compound 126 was used instead of Compound 22.¹H-NMR (CDCl₃) δ 8.91 (1H, m), 7.82 (1H, m), 7.2-7.0 (11H, m), 6.4 (1H,m), 6.2 (1H, m), 5.23-5.05 (2H, m), 4.44 (2H, s), 4.44 (1H, m), 4.2 (1H,m), 3.95 (1H, m), 3.32 (1H, m), 2.98 (3H, s), 2.8-2.5 (7H, m), 2.15 (1H,m), 1.7-1.2 (10H, m), 0.88 (6H, m). m/z 719.3 (M+H)⁺

Preparation of Example CI

Compound 127

Compound 127 (110 mg) was prepared following the procedure used toprepare Compound 126, except that Compound 8 was used instead ofCompound 125. m/z 424.4 (M+H)⁺

Example CI

Example CI (7 mg) was prepared following the procedure used to prepareExample C, except that Compounds 127 and 29 were used instead ofCompounds 8 and 7. ¹H-NMR (CDCl₃) δ 9.0 (1H, s), 8.92 (1H, s), 7.4-7.0(11H, m), 5.25 (2H, m), 4.6-4.0 (5H, m), 3.4 (1H, m), 3.1-2.6 (10H, m),1.9 (1H, m), 1.8 (10H, m), 0.9 (6H, m); m/z 719.2 (M+H)⁺

Preparation of Compound CJ

Compound 128

To a solution of Compound 21 (100 mg) in dichloromethane (5 mL) wasadded TFA (1 mL). The mixture was stirred for 3 hours, and excessreagents were evaporated. The oil was diluted with EtOAc, and then waswashed with saturated Na₂CO₃ solution (2×), water (2×), and brine, anddried over Na₂SO₄. Concentration gave Compound 128 (46 mg). m/z 267.1(M+H)⁺

Compound 129

Compound 129 (44 mg) was prepared following the procedure for Compound8, except that Compound 128 was used instead of Compound 22. m/z 408.10(M+H)⁺

Example CJ

Example CJ (55 mg) was prepared following the procedure for Example C,except that Compounds 129 and 29 were used instead of Compounds 8 and 7.¹H-NMR (CDCl₃) δ 8.81 (1H, s), 7.85 (1H, s), 7.2-7.0 (11H, m), 6.4 (1H,m), 6.12 (1H, m), 5.44 (2H, m), 5.26 (2H, s), 4.85 (1H, m), 4.70 (1H,m), 4.4 (3H, m), 4.06 (1H, m), 3.25 (1H, m), 2.98 (3H, s), 2.78 (4H, m),2.21 (1H, m), 1.38 (6H, m), 0.88 (6H, m); m/z 703.2 (M+H)⁺

Preparation of Compounds CK and CL

Example CK

Example CK (88 mg) was prepared following the procedure used to prepareExample C, except that Compound 49 was used instead of Compound 7. m/z749.2 (M+H)⁺

Example CL

A mixture of Example CK (85 mg) and TFA (5 mL) was stirred for 3 hours.Excess TFA was evaporated and the mixture was dried under high vacuum.The mixture was dissolved in THF (5 mL), and 1.0 N sodium hydroxidesolution was added until the pH was 11. The solution was stirred for 10minutes, and extracted with EtOAc. The organic phase was washed withwater, brine, and dried over Na₂SO₄.

Concentration and purification by flash column chromatography (EtOAc)gave Example CL (66 mg). ¹H-NMR (CDCl₃) δ 8.81 (1H, s), 7.84 (1H, s),7.30-6.96 (11H, m), 5.22 (2H, s), 4.90 (1H, m), 4.45 (1H, m), 4.35-4.0(4H, m), 3.8 (1H, m), 3.6 (1H, m), 3.21 (1H, m), 2.95 (3H, s), 2.8-2.6(4H, m), 2.0-1.4 (4H, m), 1.25 (6H, m). m/z 693.2 (M+H)⁺.

Preparation of Example CM

Compound 130

Compound 130 is commercially available from (TCI), and was used asreceived.

Compound 131

To the solution of Compound 130 (510 mg, 3 mmol) in methanol (12 mL) at0° C. was added thionyl chloride (0.5 mL, 6.6 mmol), dropwise. Themixture was stirred at 0° C. for 30 minutes and brought to reflux for 3hours. Concentration gave Compound 131 as a white solid.

Compound 132

To a stirred solution of Compound 131 (3 mmol) and diisopropylethylamine(2 mL, 12 mmol) in dichloromethane (35 mL) was added CDI (486 mg, 3mmol). The mixture was stirred for 12 hours. Compound 9 was added, andthe mixture was stirred for 12 additional hours. Concentration andpurification by flash column chromatography (CH₂Cl₂/iPrOH=10/1) gaveCompound 132 (414 mg). m/z 380.0 (M+H)⁺

Compound 133

Compound 133 was prepared following the procedure for Compound 67,except that Compound 132 was used instead of Compound 66. m/z 364.0(M−H)⁻

Example CM

Example CM (600 mg) was prepared following the procedure for Example C,except Compound 133 was used instead of Compound 7. ¹H-NMR (CDCl₃) δ9.18 (1H, s), 8.35 (1H, s), 7.95 (1H, s), 7.6 (1H, m), 7.3-7.0 (11H, m),5.22 (2H, m), 4.70 (1H, m), 4.50 (2H, m), 4.05 (1H, m), 3.86 (3H, s),3.80 (2H, m), 3.55 (1H, m), 3.10 (1H, m), 2.90 (3H, s), 2.70 (4H, m),1.45 (10H, m); m/z 757.3 (M+H)⁺

Preparation of Examples O, P, CN, and CO

Example O

Example O (17 mg) was prepared following the procedure for Example C,except Compounds 46 and 49 were used instead of Compounds 8 and 7. m/z749.3 (M+H)⁺

Example CN

Example CN (22 mg) was prepared following the procedure used to prepareExample C, except Compounds 46 and 13e were used instead of Compounds 8and 7. m/z 763.2 (M+H)⁺

Example P

Example P (12 mg) was prepared following the procedure used to prepareExample CM, except Example O was used instead of Example CL. ¹H-NMR(CDCl₃) δ 8.76 (1H, s), 7.79 (1H, s), 7.25-6.9 (11H, m), 6.51 (1H,broad), 5.42 (1H, m), 5.18 (2H, m), 4.42 (2H, m), 4.22 (1H, m), 4.10(1H, m), 3.95 (1H, m), 3.79 (1H, m), 3.58 (1H, m), 3.23 (1H, m), 2.93(3H, s), 2.9-2.5 (4H, m), 1.6-1.2 (10H, m); m/z: 693.2 (M+H)⁺.

Compound CO

Example CO (13 mg) was prepared following the procedure used to prepareExample CL, except Example CN was used instead of Compound CK. ¹H-NMR(CDCl₃) δ 8.85 (1H, m), 7.88 (1H, m), 7.3-7.0 (11H, m), 6.55 (1H, m),6.24 (1H, m), 5.45 (1H, m), 5.23 (2H, m), 4.6 (2H, m), 4.2 (1H, m), 4.0(2H, m), 3.7 (1H, m), 3.5 (1H, m), 3.02 (3H, s), 2.70 (4H, m), 1.6-1.0(13H, m); m/z: 707.3 (M+H)⁺.

Preparation of Examples CP-CS

Compound 134

Compound 134 was prepared using procedure described for Compound 76,except that CBZ-D-alaminol was used instead of CBZ-L-alaminol.

Compound 135

Compound 135 was prepared following the procedure used to prepareCompound 8, except Compound 134 was used instead of Compound 22.

Example CP

Example CP (12 mg) was prepared following the procedure used to prepareExample C, except Compounds 135 and 49 were used instead of Compounds 8and 7. m/z 597.2 (M+H)⁺.

Example CQ

Example CQ (11 mg) was prepared following the procedure used to prepareExample C, except Compounds 135 and 13d were used instead of Compounds 8and 7. m/z 611.2 (M+H)⁺.

Example CR

Example CR (7 mg) was prepared following the procedure used to prepareExample P, except that Example CP was used instead of Example O. ¹H-NMR(CDCl₃) δ 8.82 (1H, s), 7.88 (1H, s), 7.02 (1H, s), 6.92 (1H, m), 5.28(2H, s), 5.10 (1H, m), 4.5 (2H, m), 4.15 (2H, m), 3.88 (1H, m), 3.8-3.5(2H, m), 3.35 (1H, m), 3.0 (3H, s), 1.5-1.0 (16H, m); m/z: 541.1 (M+H)⁺.

Example CS

Example CS (8 mg) was prepared following the procedure used to prepareExample CO, except that Example CQ was used instead of Example CN.¹H-NMR (CDCl₃) δ 8.83 (1H, s), 7.88 (1H, s), 6.98 (1H, s), 6.81 (1H, m),6.58 (1H, m), 5.28 (2H, s), 5.18 (1H, m), 4.4-4.3 (2H, m), 4.03 (1H, m),3.85 (1H, m), 3.58 (2H, m), 3.3 (1H, m), 2.99 (3H, s), 1.5-0.98 (19H,m); m/z: 555.2 (M+H)⁺.

Preparation of Examples CT-CV

Compound 136

Compounds 136a-c are commercially available (Sigma-Aldrich).

Compound 137

To a solution of Compound 136 (20 mmol) in methanol (25 mL) was addedbenzaldehyde (40 mmol) dropwise. The mixture was stirred for 2 hours andwas cooled to 0° C. Sodium borohydride (44 mmol) was added in portions.The mixture was warmed to 25° C. and stirred for 2 hours. Acetic acid(10 mL) was added and the mixture was stirred for 10 minutes. Methanolwas removed and the mixture was partitioned between EtOAc and 3 N NaOHsolution. The organic layer was separated and water phase was extractedwith EtOAc (2×). The combined organic layers was washed with water,brine, and dried over Na₂SO₄. Concentration gave Compound 137.

Compound 138

Compound 138 was prepared following the procedure used to prepareCompound 8, except that Compound 137 was used instead of Compound 22.

Example CT

Example CT (70 mg) was prepared following the procedure used to prepareExample C, except that Compounds 29 and 138a was used instead ofCompounds 13a and 8. ¹H-NMR (CDCl₃) δ 8.79 (1H, s), 7.86 (1H, s), 6.97(1H, s), 6.49 (1H, m), 6.15 (1H, m), 5.28 (2H, s), 5.20 (1H, m), 4.44(2H, m), 4.05 (1H, m), 3.25 (5H, m), 3.0 (3H, s), 2.24 (1H, m), 1.8-1.45(4H, m), 1.38 (6H, m), 0.97 (6H, m); m/z: 525.2 (M+H)⁺.

Example CU

Example CU (140 mg) was prepared following the procedure used to prepareExample C, except that Compounds 29 and 138b was used instead ofCompounds 13a and 8. ¹H-NMR (CDCl₃) δ 8.78 (1H, s), 7.85 (1H, m),7.4-7.05 (10H, m), 6.93 (1H, s), 5.90 (1H, m), 5.35 (2H, s), 4.9-4.6(2H, m), 4.6-4.4 (4H, m), 4.2 (1H, m), 3.4-3.05 (5H, m), 3.0 (3H, s),2.0 (1H, m), 1.8-1.3 (10H, m), 0.90 (6H, m); m/z: 705.2 (M+H)⁺.

Example CV

Example CV (145 mg) was prepared following the procedure used to prepareExample C, except that Compounds 29 and 138c was used instead ofCompounds 13a and 8. ¹H-NMR (CDCl₃) δ 8.76 (1H, m), 7.86 (1H, m),7.4-7.02 (10H, m), 6.97 (1H, m), 5.75 (1H, m), 5.38 (2H, m), 4.95-4.3(6H, m), 4.15 (1H, m), 3.4-3.0 (5H, m), 3.0 (3H, s), 2.2-1.6 (3H, m),1.4 (6H, m), 0.88 (6H, m); m/z: 691.2 (M+H)⁺.

Preparation of Example CW

Example CW could be prepared, e.g. by reacting Compound 8 with acompound having the following structure:

where “LG” is a leaving group such as a halogen. Such compounds could beprepared by one-carbon degradation of the corresponding carboxylic acidor ester (e.g., Compounds 28 or 29) by known methods such as theHunsdieker reaction or the Kochi reaction or similar methods.IC₅₀ Determinations for Human Liver Cytochrome P450Materials and General Methods

Pooled (n≧15 donors) human hepatic microsomal fraction was obtained fromBD-Gentest (Woburn, Mass.) who also supplied hydroxy-terfenadine,4′-hydroxydiclofenac and NADPH regenerating system. Ritonavir wasprepared from commercial Norvir® oral solution (Abbott Laboratories,Abbott Park, Ill.). Other reagents were from Sigma-Aldrich (St. Louis,Mo.) and included terfenadine, fexofenadine, BRL 15572, diclofenac andmefenamic acid.

Incubations were performed in duplicate in 50 mM potassium phosphatebuffer, pH 7.4 with NADPH regenerating system used as described by themanufacturer. The final microsomal protein concentrations had previouslybeen determined to be within the linear range for activity and resultedin less than 20% consumption of substrate over the course of theincubation. The final substrate concentrations used were equal to theapparent Km values for the activities determined under the sameconditions. Inhibitors were dissolved in DMSO, and the finalconcentration of DMSO, from both substrate and inhibitor vehicles, was1% (v/v). Incubations were performed at 37° C. with shaking and wereinitiated by addition of substrate. Aliquots were then removed at 0, 7and 15 minutes. Samples were quenched by treatment with an acetonitrile,formic acid, water (94.8%/0.2%/5%, v/v/v) mixture containing internalstandard. Precipitated protein was removed by centrifugation at 3000 rpmfor 10 min and aliquots of the supernatant were then subjected to LC-MSanalysis.

The LC-MS system consisted of a Waters Acquity HPLC, with a binarysolvent manager and a refrigerated (8° C.) sample organizer and samplemanager, interfaced to a Micromass Quattro Premier tandem massspectrometer operating in electrospray ionization mode. The column was aWaters Acquity UPLC BEH C₁₈ 2.1×50 mm, 1.7 μm pore size. Mobile phasesconsisted of mixtures of acetonitrile, formic acid and water, thecomposition for mobile phase A being 1%/0.2%/98.8% (v/v/v) and that formobile phase B being 94.8%/0.2%/5% (v/v/v). The injection volumes were 5μL and the flow rate was 0.8 mL/min. Concentrations of metabolites weredetermined by reference to standard curves generated with authenticanalytes under the same conditions as the incubations.

IC₅₀ values (the concentration of inhibitor reducing CYP3A activity by50%) were calculated by non-linear regression using GraphPad Prism 4.0software and a sigmoidal model.

CYP3A Inhibition Assay

The potencies of the compounds as inhibitors of human hepaticcytochromes P450 of the CYP3A subfamily (particularly CYP3A4) wereassessed using terfenadine oxidase, a well-characterized CYP3A-selectiveactivity described in Ling, K.-H. J., et al Drug Metab. Dispos. 23,631-636, (1995) and Jurima-Romet, et al Drug Metab. Dispos. 22, 849-857,(1994). The final concentrations of microsomal protein and terfenadinesubstrate were 0.25 mg/mL and 3 mM, respectively. Metabolic reactionswere terminated by treatment with seven volumes of quench solutioncontaining 0.1 μM BRL 15572 as internal standard. A further 8 volumes ofwater were added before centrifugation and aliquots of the supernatantwere removed for analysis.

For LC-MS analysis chromatographic elution was achieved by a series oflinear gradients starting at 20% B and holding for 0.1 minutes, thenincreasing to 80% B over 1.5 minutes, holding for 0.4 minutes and thenreturning to the starting conditions for 0.05 min. The system wasallowed to re-equilibrate for at least 0.25 minutes prior to the nextinjection. The mass spectrometer was operated in positive ion mode andthe following precursor ([M+H]⁺)/product ion pairs were monitored andquantified using MassLynx 4.0 (SP4, 525) software: hydroxy-terfenadine488.7/452.4, fexofenadine 502.7/466.4 and BRL 15572 407.5/209.1.Terfenadine oxidase activity was determined from the sum ofhydroxy-terfenadine and carboxy-terfenadine (fexofenadine) metabolites.

CYP2C9 Inhibition Assay

The potencies of the compounds as inhibitors of human hepatic CYP2C9were assessed using diclofenac 4′-hydroxylase, an activity specific forthis enzyme, as described in Leeman, T., et al Life Sci. 52, 29-34,(1992). The final concentrations of microsomal protein and diclofenacsubstrate were 0.08 mg/mL and 4 μM, respectively. Metabolic reactionswere terminated by treatment with three volumes of quench solutioncontaining 1 μM mefenamic acid as internal standard. Aftercentrifugation a further 4 volumes of water were added. Aliquots of thesupernatant were then subjected to LC-MS analysis.

For LC-MS analysis chromatographic elution was achieved by a series oflinear gradients starting at 20% B and holding for 0.3 minutes, thenincreasing to 99% B over 1.2 minutes, holding for 0.5 minutes and thenreturning to the starting conditions for 0.25 min. The system wasallowed to re-equilibrate for at least 0.25 minutes prior to the nextinjection. The mass spectrometer was operated in negative ion mode andthe following precursor ([M−H]⁻)/product ion pairs were monitored andquantified: 4′-hydroxy-diclofenac 312.4/294.2 and mefenamic acid242.4/224.2.

Biological Assays Used for the Characterization of HIV ProteaseInhibitors

HIV-1 Protease Enzyme Assay (Ki)

The assay is based on the fluorimetric detection of synthetichexapeptide substrate cleavage by HIV-1 protease in a defined reactionbuffer as initially described by M. V. Toth and G. R. Marshall, Int. J.Peptide Protein Res. 36, 544 (1990) (herein incorporated by reference inits entirety for all purposes).

The assay employed (2-aminobenzoyl)Thr-Ile-Nle-(p-nitro)Phe-Gln-Arg asthe substrate and recombinant HIV-1 protease expressed in E. Coli as theenzyme. Both of the reagents were supplied by Bachem California, Inc.(Torrance, Calif.; Cat. no. H-2992). The buffer for this reaction was100 mM ammonium acetate, pH 5.3, 1 M sodium chloride, 1 mMethylendiaminetetraacetic acid, 1 mM dithiothreitol, and 10%dimethylsulfoxide.

To determine the inhibition constant K_(i), a series of solutions wereprepared containing identical amount of the enzyme (1 to 2.5 nM) and theinhibitor to be tested at different concentrations in the reactionbuffer. The solutions were subsequently transferred into a white 96-wellplate (190 μl each) and preincubated for 15 min at 37° C. The substratewas solubilzed in 100% dimethylsulfoxide at a concentration of 800 μMand 10 μl of 800 μM substrate was added into each well to reach a finalsubstrate concentration of 40 μM. The real-time reaction kinetics wasmeasured at 37° C. using a Gemini 96-well plate fluorimeter (MolecularDevices, Sunnyvale, Calif.) at λ(Ex)=330 nm and λ(Em)=420 nm. Initialvelocities of the reactions with different inhibitor concentrations weredetermined and the K_(i) value (in picomolar concentration units) wascalculated by using EnzFitter program (Biosoft, Cambridge, U.K.)according to an algorithm for tight-binding competitive inhibitiondescribed by Ermolieff J., Lin X., and Tang J., Biochemistry 36, 12364(1997).

HIV-1 Protease Enzyme Assay (IC50)

As for the K_(i) assay, above, the IC₅₀ assay is based on thefluorimetric detection of synthetic hexapeptide substrate cleavage byHIV-1 protease in a defined reaction buffer as initially described by M.V. Toth and G. R. Marshall, Int. J. Peptide Protein Res. 36, 544 (1990).

The assay employed (2-aminobenzoyl)Thr-Ile-Nle-(p-nitro)Phe-Gln-Arg asthe substrate and recombinant HIV-1 protease expressed in E. Coli as theenzyme. Both of the reagents were supplied by Bachem California, Inc.(Torrance, Calif.; Cat. nos. H-2992 and H-9040, respectively). Thebuffer for this reaction was 100 mM ammonium acetate, pH 5.5, 1 M sodiumchloride, 1 mM ethylendiaminetetraacetic acid, and 1 mM dithiothreitol,and 10% dimethylsulfoxide.

To determine the IC50 value, 170 μL of reaction buffer was transferredinto the wells of a white 96-well microtiter plate. A series of 3-folddilutions in DMSO of the inhibitor to be tested was prepared, and 10 μLof the resulting dilutions was transferred into the wells of themicrotiter plate. 10 μL of a 20-50 nM enzyme stock solution in reactionbuffer was added to each well of the 96-well plate to provide a finalenzyme concentration of 1-2.5 nM. The plates were then preincubated for10 minutes at 37° C. The substrate was solubilzed in 100%dimethylsulfoxide at a concentration of 400 μM and 10 μl of the 400 μMsubstrate was added into each well to reach a final substrateconcentration of 20 μM. The real-time reaction kinetics were measuredusing a Gemini 96-well plate fluorimeter (Molecular Devices, Sunnyvale,Calif.) at λ(Ex)=330 nm and λ(Em)=420 nm. Initial velocities of thereactions with different inhibitor concentrations were determined andthe IC₅₀ value (in nanomolar concentration units) was calculated byusing GraphPad Prism™ software to fit nonlinear regression curves.

Anti-HIV-1 Cell Culture Assay (EC50)

The assay is based on quantification of the HIV-1-associated cytopathiceffect by a calorimetric detection of the viability of virus-infectedcells in the presence or absence of tested inhibitors. HIV-1-inducedcell death was determined using a metabolic substrate2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide(XTT) which is converted only by intact cells into a product withspecific absorption characteristics as described by Weislow O S, KiserR, Fine D L, Bader J, Shoemaker R H and Boyd M R, J. Natl. Cancer Inst.81, 577 (1989) (herein incorporated by reference in its entirety for allpurposes).

MT2 cells (NIH AIDS reagent program, Cat # 237) maintained in RPMI-1640medium supplemented with 5% fetal bovine serum and antibiotics wereinfected with the wild-type HIV-1 strain IIIB (Advanced Biotechnologies,Columbia, Md.) for 3 hours at 37° C. using the virus inoculumcorresponding to a multiplicity of infection equal to 0.01. The infectedcells in culture media were distributed into a 96-well plate (20,000cells in 100 μl/well), and incubated in the presence of a set ofsolutions containing 5-fold serial dilutions of the tested inhibitor(100 μl/well) for 5 days at 37° C. Samples with untreated infected anduntreated mock-infected control cells were also distributed to the96-well plate and incubated under the same conditions.

To determine the antiviral activity of the tested inhibitors, asubstrate XTT solution (6 mL per assay plate) at a concentration of 2mg/mL in a phosphate-buffered saline pH 7.4 was heated in water-bath for5 min at 55° C. before 50 μl of N-methylphenazonium methasulfate (5μg/mL) was added per 6 mL of XTT solution. After removing 100 μl mediafrom each well on the assay plate, 100 μl of the XTT substrate solutionwas added to each well. The cells and the XTT solution were incubated at37° C. for 45 to 60 min in a CO₂ incubator. To inactivate the virus, 20μl of 2% Triton X-100 was added to each well. Viability, as determinedby the amount of XTT metabolites produced, was quantifiedspectrophotometrically by the absorbance at 450 nm (with subtraction ofthe background absorbance at 650 nm). Data from the assay was expressedas the percentage absorbance relative to untreated control and the fiftypercent effective concentration (EC₅₀) was calculated as theconcentration of compound that effected an increase in the percentage ofXTT metabolite production in infected, compound treated cells to 50% ofthat produced by uninfected, compound-free cells.

Anti-HIV-1 Cell Culture Assay (EC₅₀) in Presence of 40% Human Serum orHuman Serum Proteins

This assay is almost identical to the Anti-HIV-1 Cell Culture Assaydescribed above, except that the infection was made in the presence orabsence of 40% human serum (Type AB Male Cambrex 14-498E) or human serumproteins (Human α-acid Glycoprotein, Sigma G-9885; Human Serum Albumin,Sigma A1653, 96-99%) at physiological concentration. The HIV-1-inducedcell death was determined as described above, except that the infectedcells distributed in the 96-well plate were incubated in 80% Human Serum(2× concentration) or in 2 mg/mL Human α-acid Glycoprotein+70 mg/mL HSA(2× concentration) rather than in culture media.

Cytotoxicity Cell Culture Assay (CC₅₀)

The assay is based on the evaluation of cytotoxic effect of testedcompounds using a metabolic substrate2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide(XTT) as described by Weislow O S, Kiser R, Fine D L, Bader J, ShoemakerR H and Boyd M R, J. Natl. Cancer Inst. 81, 577 (1989). This assay isalmost identical to the previous assay described (Anti-HIV-1 CellCulture Assay), except that the cells were not infected. The compoundinduced cell death (or growth reduction) was determined as previouslydescribed.

MT-2 cells maintained in RPMI-1640 medium supplemented with 5% fetalbovine serum and antibiotics were distributed into a 96-well plate(20,000 cells in 100 μl/well) and incubated in the presence or absenceof 5-fold serial dilutions of the tested inhibitor (100 μl/well) for 5days at 37° C. Controls included untreated infected cells and infectedcells protected by 1 μM of P4405 (Podophyllotoxin, Sigma Cat # P4405).

To determine cytotoxicity, an XTT solution (6 mL per assay plate) at aconcentration of 2 mg/mL in phosphate-buffered saline pH 7.4 was heatedin the dark in a water-bath for 5 min at 55° C. before 50 μl ofN-methylphenazonium methasulfate (5 μg/mL) was added per 6 mL of XTTsolution. After removing 100 μL media from each well on the assay plate,100 μL of the XTT substrate solution was added to each well. The cellsand the XTT solution were incubated at 37° C. for 45 to 60 min in a CO₂incubator. To inactivate the virus, 20 μl of 2% Triton X-100 was addedto each well. Viability, as determined by the amount of XTT metabolitesproduced, is quantified spectrophotometrically by the absorbance at 450nm (with subtraction of the background absorbance at 650 nm). Data fromthe assay is expressed as the percentage absorbance relative tountreated control, and the fifty percent cytotoxicity concentration(EC₅₀) was calculated as the concentration of compound that effected anincrease in the percentage of cell growth in compound treated cells to50% of the cell growth provided by uninfected, compound-free cells.

Experimental data based on representative Examples A-CV demonstrate thatthe compounds of Formula (I) of the present invention can have a CYP4503A4 inhibition activity in a range represented by an IC₅₀ from about 100nM to about 4700 nM, and a CYP450 2C9 inhibition activity in a rangerepresented by an IC₅₀ from about 100 nM to about 4200 nM.

Experimental data based on representative Examples A-CV demonstrate thatthe compounds of Formula (I) of the present invention can have aprotease inhibition activity in a range represented by HIV EC₅₀ fromabout 140 nM to greater than about 1000 nM.

Experimental data based on representative Examples P, S, and T have aCYP450 3A4 inhibition activity in a range represented by an IC₅₀ fromabout 80-150 nM, a CYP450 2C9 inhibition activity in a range representedby an IC₅₀ from about 1000-10,000 nM, and a protease inhibition activityin a range represented by HIV EC₅₀ greater than about 20,000 nM.

1. A compound of formula IID,

or a pharmaceutically acceptable salt thereof, wherein, L¹ is selectedfrom the group consisting of —C(R⁶)₂—, —C(O)—, —S(O₂)—, —N(R⁷)—C(O)—,and —O—C(O)—; each L³ is independently a covalent bond, alkylene, orsubstituted alkylene; each L⁴ is independently selected from the groupconsisting of a covalent bond, alkylene, substituted alkylene, —O—,—CH₂—O—, and —NH—; each A is independently selected from the groupconsisting of H, alkyl, substituted alkyl, aryl, substituted aryl,heterocyclyl, and substituted heterocyclyl, with the proviso that when Ais H, p is 0; Z¹ and Z² are each independently —O— or —N(R⁷)—; Y and Xare each independently selected from the group consisting ofheterocyclyl and heterocyclylalkyl; each Ar is independently selectedfrom the group consisting of aryl, substituted aryl, heteroaryl, andsubstituted heteroaryl; R¹, R³, and R⁵ are each independently selectedfrom the group consisting of H, alkyl, substituted alkyl, arylalkyl, andsubstituted arylalkyl; R² is independently selected from the groupconsisting of H, alkyl, substituted alkyl, alkoxyalkyl, hydroxyalkyl,arylheteroalkyl, substituted arylheteroalkyl, arylalkyl, substitutedarylalkyl, heterocyclylalkyl, substituted heterocyclylalkyl, aminoalkyl,substituted aminoalkyl, -alkylene-C(O)—OH, -alkylene-C(O)—Oalkyl,-alkylene-C(O)amino, and -alkylene-C(O)-alkyl; R⁴ and R⁶ are eachindependently selected from the group consisting of H, alkyl,substituted alkyl, and heteroalkyl; each R⁷ is independently selectedfrom the group consisting of H, alkyl, substituted alkyl, heteroalkyl,carbocyclyl, substituted carbocyclyl, heterocyclyl, and substitutedheterocyclyl; R⁸ and R⁹ are each one or more substituents independentlyselected from the group consisting of H, alkyl, substituted alkyl,halogen, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl,and —CN; and each p is independently 0 or
 1. 2. The compound of claim 1,wherein: L¹ is —C(R⁶)₂—; each L³ is alkylene; each A is aryl orsubstituted aryl; X and Y are each heterocyclylalkyl; Z¹ is —N(R⁷)—; andZ² is —O—.
 3. A compound which is:

or a pharmaceutically acceptable salt thereof.
 4. A pharmaceuticalcomposition comprising the compound or salt of formula IID as describedin claim 1 and a pharmaceutically acceptable carrier or excipient. 5.The pharmaceutical composition of claim 4, further comprising at leastone additional therapeutic agent.
 6. The pharmaceutical composition ofclaim 5, wherein the at least one additional therapeutic agent ismetabolized by cytochrome P450 monooxygenase.